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Qi Z, Lin S, Yu Q, Ma R, Zhang K, Jiang W, Chen S, Mai Y, Fu QB. Human neutrophil defensin-1 binding increases histidine kinase activity of SaeS in Staphylococcus aureus. Biochem Biophys Rep 2025; 42:101982. [PMID: 40207086 PMCID: PMC11981803 DOI: 10.1016/j.bbrep.2025.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 03/06/2025] [Accepted: 03/17/2025] [Indexed: 04/11/2025] Open
Abstract
Human neutrophil defensin-1 (HNP-1) can specifically activate the SaeRS two-component system(TCS), which is essential for controlling virulence and immune evasion factors in Staphylococcus aureus. The reaction to HNP1 requires the transmembrane domain of SaeS (SaeS™), however the precise mechanism is yet unknown. In this work, we reconstructed the SaeS™ protein into bicelles and discovered that HNP1 can interact directly with SaeS™ using BiacoreT200, their binding significantly increases SaeS kinase activity and activated the SaeRS system subsequently. Staphylococcus aureus may exploit host-derived factors released by human immune cells to activate its two-component signal transduction system, thereby enhancing antimicrobial peptide resistance.
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Affiliation(s)
- Zhengfei Qi
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Shuru Lin
- College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Quanxiang Yu
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Rui Ma
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Kexin Zhang
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Wenqi Jiang
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Shurong Chen
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Yilin Mai
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Qingshan Bill Fu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
- Shanghai Institute of Materia Medica, Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan, 528400, China
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Li M, An Z, Yu M, Zhou X, Yang Z, Chen Z. Brazilin reduces methicillin-resistant Staphylococcus aureus virulence and pathogenicity by decreasing the secretion of the α-hemolysin. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156616. [PMID: 40068293 DOI: 10.1016/j.phymed.2025.156616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 02/25/2025] [Accepted: 03/05/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Methicillin-resistant Staphylococcus aureus (MRSA) is a super-resistant bacterium with strong pathogenicity, causing broad range of infections in various tissues. α-Hemolysin (Hla) is the main virulence factor of S. aureus. Brazilin (BN), is a homoisoflavonoid derivative, obtained from the wood of Caesalpinia echinata Lam (Brazil-wood), Caesalpinia sappan L (Leguminosae), and Caesalpinia violacea Standl, has been proven to exert excellent antibacterial and anti-virulence effects against S. aureus. However, the underlying mechanisms remain still unclear. OBJECTIVE This study aims to evaluate the inhibitory effect of BN on MRSA virulence and pathogenicity and elucidate its underlying mechanisms. METHODS Rabbit erythrocytes were used to evaluate the effect of BN on hemocytolysis. The potential target of BN was screened by transcriptomic sequencing and verified by qRT-PCR, western blot (WB), and molecular interaction experiments. The effects of BN on MRSA toxicity and pathogenicity were both validated using A549 cell and mouse skin abscess model caused by MRSA. RESULTS BN attenuated the hemolytic activity of MRSA by inhibiting Hla secretion. It was also found that BN blocks its binding to the P1 promoter of the sae operon, and then reduced its transcript level. Remarkably, ΔsaeR strain exhibits significantly reduced hemolytic activity due to impaired regulation of Hla and no extra inhibitory effect was observed in the samples treated with BN. Moreover, BN relieved A549 cell damage and mouse skin abscess induced by MRSA by inhibiting SaeR. CONCLUSION These findings reveal, for the first time, BN can alleviate MRSA virulence and pathogenicity by decreasing the secretion of the Hla via inhibiting SaeR. Overall, this study suggests that BN could be a candidate for being submitted to further studies with the aim of its development as a new antibiotic against MRSA.
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Affiliation(s)
- Mingzhe Li
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou 563003, China; School of Laboratory Medicine, Zunyi Medical University, Zunyi Guizhou 563006, China
| | - Zhengyuan An
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou 563003, China
| | - Mengfei Yu
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou 563003, China
| | - Xiaoxian Zhou
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou 563003, China
| | - Zhifang Yang
- The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Zehui Chen
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou 563003, China; School of Laboratory Medicine, Zunyi Medical University, Zunyi Guizhou 563006, China.
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Jiang T, Zhu X, Yin Z, Gao R, Li Y, Li C, Meng Q, Zhu X, Song W, Su X. Dual role of Baimao-Longdan-Congrong-Fang in inhibiting Staphylococcus aureus virulence factors and regulating TNF-α/TNFR1/NF-κB/MMP9 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156477. [PMID: 39938176 DOI: 10.1016/j.phymed.2025.156477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/01/2025] [Accepted: 02/04/2025] [Indexed: 02/14/2025]
Abstract
BACKGROUND Baimao-Longdan-Congrong-Fang (BLCF), a traditional Chinese herbal formula described in the Taiping Shenghui Fang (998 AD), consists of medicinal plants with heat-clearing and tonifying properties. BLCF has a promise as a treatment for Staphylococcus aureus (S. aureus) pneumonia, according to its historical use and current pharmacological research. PURPOSE In this study, the inhibitory effects of BLCF on S. aureus virulence factors were evaluated in vitro, and its mechanisms of action were investigated in a methicillin-resistant S. aureus (MRSA) pneumonia mouse model. METHODS The inhibitory effect of BLCF on S. aureus virulence factors, including sortase A (SrtA) and α-hemolysin (Hla), was investigated by fluorescence resonance energy transfer (FRET) and hemolysis assays. A C57BL/6J mouse model of MRSA pneumonia was employed to evaluate its therapeutic efficacy. Accordingly, an integrated strategy of medicinal chemistry, network pharmacology analysis, GEO database analysis, bioinformatics, molecular docking, molecular dynamics simulation, GeneMANIA-based functional association (GMFA), and GSEA was used to identify and illustrate potential therapeutic targets and mechanisms. Subsequently, the mechanistic results were confirmed by Western blot analysis and RT-qPCR. RESULTS While BLCF exhibited weak inhibitory activity against S. aureus USA300, Newman, and SA37 strains, it significantly suppressed SrtA-related virulence functions without affecting bacterial growth. FRET and hemolysis assays confirmed that BLCF inhibited SrtA activity (IC50 = 1.25 mg/mL) while decreasing hemolytic activity. Furthermore, BLCF protected mice from MRSA infection, increasing their survival rates. Bioinformatics analysis identified 26 active compounds and 2 hub genes (Tnf and Mmp9) that were associated with 5 types of immune cell, including activated CD4 T cells, myeloid-derived suppressor cells, activated dendritic cells, macrophages, and mast cells. Molecular docking revealed 3 active compounds (isoacteoside, verbascoside, and echinacoside) that exhibited strong binding affinities to TNF, MMP9, and SrtA. Molecular dynamics simulations validated the stable interactions between isoacteoside and the target proteins, yielding binding energies of -136.76 ± 8.83 kJ/mol, -174.98 ± 14.89 kJ/mol, and -186.34 ± 9.06 kJ/mol, respectively. The therapeutic effect of BLCF was closely linked to the NF-κB signaling pathway, as revealed by GMFA and GSEA analyses. In vivo, BLCF reduced lung bacterial load, improved the wet/dry ratio, and decreased inflammatory cytokines, thereby enhancing lung histopathology through modulation of the TNF-α/TNFR1/NF-κB/MMP9 axis. CONCLUSIONS BLCF can effectively treat MRSA pneumonia in mice by inhibiting SrtA activity, decreasing hemolytic activity, and regulating the TNF-α/TNFR1/NF-κB/MMP9 axis. These findings suggest BLCF, a traditional herbal formula, as a promising novel therapeutic approach to treat pneumonia.
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Affiliation(s)
- Tao Jiang
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Xiujing Zhu
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Zixin Yin
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Rui Gao
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Yufen Li
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Chenhao Li
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Qianting Meng
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Xiaojuan Zhu
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Wu Song
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Xin Su
- Changchun University of Chinese Medicine, Changchun 130117, China.
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Lee JH, Kim YG, Choi JS, Jeong YT, Hwang BS, Lee J. Antibiofilm and Antihemolytic Activities of Actinostemma lobatum Extract Rich in Quercetin against Staphylococcus aureus. Pharmaceutics 2024; 16:1075. [PMID: 39204420 PMCID: PMC11359957 DOI: 10.3390/pharmaceutics16081075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/01/2024] [Accepted: 08/13/2024] [Indexed: 09/04/2024] Open
Abstract
Staphylococcus aureus biofilm formation is a pivotal mechanism in the development of drug resistance, conferring resilience against conventional antibiotics. This study investigates the inhibitory effects of Actinostemma lobatum (A. lobatum) Maxim extracts on S. aureus biofilm formation and their antihemolytic activities, with a particular focus on identifying the active antibiofilm and antihemolysis compound, quercetin. Seven solvent extracts and twelve sub-fractions were evaluated against four S. aureus strains. The ethyl acetate fraction (10 to 100 μg/mL) significantly hindered biofilm formation by both methicillin-sensitive and -resistant strains. Bioassay-guided isolation of the ethyl acetate extract identified quercetin as the major antibiofilm compound. The ethyl acetate extract was found to contain 391 μg/mg of quercetin and 30 μg/mg of kaempferol. Additionally, the A. lobatum extract exhibited antihemolytic activity attributable to the presence of quercetin. The findings suggest that quercetin-rich extracts from A. lobatum and other quercetin-rich foods and plants hold promise for inhibiting resilient S. aureus biofilm formation and attenuating its virulence.
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Affiliation(s)
- Jin-Hyung Lee
- School of Chemical Engineering, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, Republic of Korea; (J.-H.L.); (Y.-G.K.)
| | - Yong-Guy Kim
- School of Chemical Engineering, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, Republic of Korea; (J.-H.L.); (Y.-G.K.)
| | - Ji-Su Choi
- Nakdonggang National Institute of Biological Resources, 137, Donam 2-gil, Sangju-si 37242, Republic of Korea; (J.-S.C.); (Y.T.J.)
| | - Yong Tae Jeong
- Nakdonggang National Institute of Biological Resources, 137, Donam 2-gil, Sangju-si 37242, Republic of Korea; (J.-S.C.); (Y.T.J.)
| | - Buyng Su Hwang
- Nakdonggang National Institute of Biological Resources, 137, Donam 2-gil, Sangju-si 37242, Republic of Korea; (J.-S.C.); (Y.T.J.)
| | - Jintae Lee
- School of Chemical Engineering, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, Republic of Korea; (J.-H.L.); (Y.-G.K.)
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Sun Z, Liu K, Liang C, Wen L, Wu J, Liu X, Li X. Diosmetin as a promising natural therapeutic agent: In vivo, in vitro mechanisms, and clinical studies. Phytother Res 2024; 38:3660-3694. [PMID: 38748620 DOI: 10.1002/ptr.8214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 04/09/2024] [Accepted: 04/13/2024] [Indexed: 07/12/2024]
Abstract
Diosmetin, a natural occurring flavonoid, is primarily found in citrus fruits, beans, and other plants. Diosmetin demonstrates a variety of pharmacological activities, including anticancer, antioxidant, anti-inflammatory, antibacterial, metabolic regulation, cardiovascular function improvement, estrogenic effects, and others. The process of literature search was done using PubMed, Web of Science and ClinicalTrials databases with search terms containing Diosmetin, content, anticancer, anti-inflammatory, antioxidant, pharmacological activity, pharmacokinetics, in vivo, and in vitro. The aim of this review is to summarize the in vivo, in vitro and clinical studies of Diosmetin over the last decade, focusing on studies related to its anticancer, anti-inflammatory, and antioxidant activities. It is found that DIO has significant therapeutic effects on skin and cardiovascular system diseases, and its research in pharmacokinetics and toxicology is summarized. It provides the latest information for researchers and points out the limitations of current research and areas that should be strengthened in future research, so as to facilitate the relevant scientific research and clinical application of DIO.
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Affiliation(s)
- Zihao Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kai Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chuipeng Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lin Wen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jijiao Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolian Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Xiong YQ, Li Y, Goncheva MI, Elsayed AM, Zhu F, Li L, Abdelhady W, Flannagan RS, Yeaman MR, Bayer AS, Heinrichs DE. The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis. J Infect Dis 2024; 229:1648-1657. [PMID: 38297970 PMCID: PMC11175694 DOI: 10.1093/infdis/jiad577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Staphylococcus aureus is the most common cause of life-threatening endovascular infections, including infective endocarditis (IE). These infections, especially when caused by methicillin-resistant strains (MRSA), feature limited therapeutic options and high morbidity and mortality rates. METHODS Herein, we investigated the role of the purine biosynthesis repressor, PurR, in virulence factor expression and vancomycin (VAN) treatment outcomes in experimental IE due to MRSA. RESULTS The PurR-mediated repression of purine biosynthesis was confirmed by enhanced purF expression and production of an intermediate purine metabolite in purR mutant strain. In addition, enhanced expression of the transcriptional regulators, sigB and sarA, and their key downstream virulence genes (eg, fnbA, and hla) was demonstrated in the purR mutant in vitro and within infected cardiac vegetations. Furthermore, purR deficiency enhanced fnbA/fnbB transcription, translating to increased fibronectin adhesion versus the wild type and purR-complemented strains. Notably, the purR mutant was refractory to significant reduction in target tissues MRSA burden following VAN treatment in the IE model. CONCLUSIONS These findings suggest that the purine biosynthetic pathway intersects the coordination of virulence factor expression and in vivo persistence during VAN treatment, and may represent an avenue for novel antimicrobial development targeting MRSA.
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Affiliation(s)
- Yan Q Xiong
- The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
- Department of Medicine, Division of Infectious Diseases, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Yi Li
- The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
| | - Mariya I Goncheva
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Ahmed M Elsayed
- The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
| | - Fengli Zhu
- The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
| | - Liang Li
- The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
| | - Wessam Abdelhady
- The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
| | - Ronald S Flannagan
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Michael R Yeaman
- The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
- Department of Medicine, Division of Infectious Diseases, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- Department of Medicine, Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
| | - Arnold S Bayer
- The Lundquist Institute for Biomedical Innovation, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
- Department of Medicine, Division of Infectious Diseases, Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - David E Heinrichs
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
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Kerro Dego O, Vidlund J. Staphylococcal mastitis in dairy cows. Front Vet Sci 2024; 11:1356259. [PMID: 38863450 PMCID: PMC11165426 DOI: 10.3389/fvets.2024.1356259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 05/06/2024] [Indexed: 06/13/2024] Open
Abstract
Bovine mastitis is one of the most common diseases of dairy cattle. Even though different infectious microorganisms and mechanical injury can cause mastitis, bacteria are the most common cause of mastitis in dairy cows. Staphylococci, streptococci, and coliforms are the most frequently diagnosed etiological agents of mastitis in dairy cows. Staphylococci that cause mastitis are broadly divided into Staphylococcus aureus and non-aureus staphylococci (NAS). NAS is mainly comprised of coagulase-negative Staphylococcus species (CNS) and some coagulase-positive and coagulase-variable staphylococci. Current staphylococcal mastitis control measures are ineffective, and dependence on antimicrobial drugs is not sustainable because of the low cure rate with antimicrobial treatment and the development of resistance. Non-antimicrobial effective and sustainable control tools are critically needed. This review describes the current status of S. aureus and NAS mastitis in dairy cows and flags areas of knowledge gaps.
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Affiliation(s)
- Oudessa Kerro Dego
- Department of Animal Science, University of Tennessee, Knoxville, TN, United States
| | - Jessica Vidlund
- Department of Animal Science, University of Tennessee, Knoxville, TN, United States
- East Tennessee AgResearch and Education Center-Little River Animal and Environmental Unit, University of Tennessee, Walland, TN, United States
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Yamazaki Y, Ito T, Tamai M, Nakagawa S, Nakamura Y. The role of Staphylococcus aureus quorum sensing in cutaneous and systemic infections. Inflamm Regen 2024; 44:9. [PMID: 38429810 PMCID: PMC10905890 DOI: 10.1186/s41232-024-00323-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/15/2024] [Indexed: 03/03/2024] Open
Abstract
BACKGROUND Staphylococcus aureus is a leading cause of human bacterial infections worldwide. It is the most common causative agent of skin and soft tissue infections, and can also cause various other infections, including pneumonia, osteomyelitis, as well as life-threatening infections, such as sepsis and infective endocarditis. The pathogen can also asymptomatically colonize human skin, nasal cavity, and the intestine. S. aureus colonizes approximately 20-30% of human nostrils, being an opportunistic pathogen for subsequent infection. Its strong ability to silently spread via human contact makes it difficult to eradicate S. aureus. A major concern with S. aureus is its capacity to develop antibiotic resistance and adapt to diverse environmental conditions. The variability in the accessory gene regulator (Agr) region of the genome contributes to a spectrum of phenotypes within the bacterial population, enhancing the likelihood of survival in different environments. Agr functions as a central quorum sensing (QS) system in S. aureus, allowing bacteria to adjust gene expression in response to population density. Depending on Agr expression, S. aureus secretes various toxins, contributing to virulence in infectious diseases. Paradoxically, expressing Agr may be disadvantageous in certain situations, such as in hospitals, causing S. aureus to generate Agr mutants responsible for infections in healthcare settings. MAIN BODY This review aims to demonstrate the molecular mechanisms governing the diverse phenotypes of S. aureus, ranging from a harmless colonizer to an organism capable of infecting various human organs. Emphasis will be placed on QS and its role in orchestrating S. aureus behavior across different contexts. SHORT CONCLUSION The pathophysiology of S. aureus infection is substantially influenced by phenotypic changes resulting from factors beyond Agr. Future studies are expected to give the comprehensive understanding of S. aureus overall profile in various settings.
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Affiliation(s)
- Yuriko Yamazaki
- Cutaneous Allergy and Host Defense, Immunology Frontier Research Center, Osaka, University, Osaka, 565-0871, Japan
- Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
| | - Tomoka Ito
- Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
| | - Masakazu Tamai
- Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
| | - Seitaro Nakagawa
- Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
| | - Yuumi Nakamura
- Cutaneous Allergy and Host Defense, Immunology Frontier Research Center, Osaka, University, Osaka, 565-0871, Japan.
- Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
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Tao Z, Ke K, Shi D, Zhu L. Development of a dual fluorescent reporter system to identify inhibitors of Staphylococcus aureus virulence factors. Appl Environ Microbiol 2023; 89:e0097823. [PMID: 37889047 PMCID: PMC10686081 DOI: 10.1128/aem.00978-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/15/2023] [Indexed: 10/28/2023] Open
Abstract
IMPORTANCE Staphylococcus aureus is a formidable pathogen responsible for a wide range of infections, and the emergence of antibiotic-resistant strains has posed significant challenges in treating these infections. In this study, we have established a novel dual reporter system capable of concurrently monitoring the activities of two critical virulence regulators in S. aureus. By incorporating both reporters into a single screening platform, we provide a time- and cost-efficient approach for assessing the activity of compounds against two distinct targets in a single screening round. This innovative dual reporter system presents a promising strategy for the identification of molecules capable of modulating virulence gene expression in S. aureus, potentially expediting the development of antivirulence therapies.
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Affiliation(s)
- Zhanhua Tao
- Institute of Eco-Environmental Research, Guangxi Academy of Sciences, Nanning, China
- Guangxi Key Laboratory of Marine Natural Products and Combinatorial Biosynthesis Chemistry, Nanning, China
| | - Ke Ke
- Guangxi Academy of Sciences, Nanning, China
| | | | - Libo Zhu
- Guangxi Academy of Sciences, Nanning, China
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Peng Q, Tang X, Dong W, Zhi Z, Zhong T, Lin S, Ye J, Qian X, Chen F, Yuan W. Carvacrol inhibits bacterial polysaccharide intracellular adhesin synthesis and biofilm formation of mucoid Staphylococcus aureus: an in vitro and in vivo study. RSC Adv 2023; 13:28743-28752. [PMID: 37807974 PMCID: PMC10552078 DOI: 10.1039/d3ra02711b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 09/25/2023] [Indexed: 10/10/2023] Open
Abstract
Staphylococcus aureus (S. aureus) is one of the important human pathogens and causes both superficial and systemic infections. More importantly, the formation of S. aureus biofilms, a main cause of its pathogenicity and drug resistance, has been a critical challenge in clinical treatment. Carvacrol, a plant-based natural product, has gained great interest for therapeutic purposes due to its effective biological activity with low cytotoxicity. The present study aimed to investigate the effect of carvacrol on anti-biofilm activity. Growth curve analysis showed that applying a sub-inhibitory concentration of carvacrol (4 μg mL-1) was not lethal to S. aureus SYN; however, the inhibition rate of biofilm formation was as high as 63.6%, and the clearance rate of mature biofilms was as high as 30.7%. In addition, carvacrol effectively reduced the production of biofilm-associated extracellular polysaccharides and showed no effect on eDNA release. Furthermore, qPCR analysis revealed that carvacrol significantly down-regulated the expression of icaA, icaB, icaC, agrA, and sarA (P < 0.05). The in vivo efficacy of carvacrol against biofilm infection was further verified with a biological model of G. mellonella larvae. The results showed that carvacrol was non-toxic to the larvae and can effectively increase the survival rate of the larvae infected with S. aureus strain SYN.
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Affiliation(s)
- Qi Peng
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
| | - Xiaohua Tang
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
- Department of Clinical Laboratory, Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150 PR China
| | - Wanyang Dong
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
| | - Ziling Zhi
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
| | - Tian Zhong
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
| | - Shunan Lin
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
| | - Jingyi Ye
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
| | - Xiping Qian
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
| | - Fu Chen
- Panyu District Health Management Center Guangzhou 511450 PR China
| | - Wenchang Yuan
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University Guangzhou 510180 PR China
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11
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Goc A, Sumera W, Rath M, Niedzwiecki A. Inhibition of α-hemolysin activity of Staphylococcus aureus by theaflavin 3,3'-digallate. PLoS One 2023; 18:e0290904. [PMID: 37651426 PMCID: PMC10470925 DOI: 10.1371/journal.pone.0290904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/17/2023] [Indexed: 09/02/2023] Open
Abstract
The ongoing rise in antibiotic resistance, and a waning of the introduction of new antibiotics, has resulted in limited treatment options for bacterial infections, including these caused by methicillin-resistant Staphylococcus aureus, leaving the world in a post-antibiotic era. Here, we set out to examine mechanisms by which theaflavin 3,3'-digallate (TF3) might act as an anti-hemolytic compound. In the presented study, we found that TF3 has weak bacteriostatic and bactericidal effects on Staphylococcus aureus, and strong inhibitory effect towards the hemolytic activity of its α-hemolysin (Hla) including its production and secretion. A supportive SPR assay reinforced these results and further revealed binding of TF3 to Hla with KD = 4.57×10-5 M. Interestingly, TF3 was also able to protect human primary keratinocytes from Hla-induced cell death, being at the same time non-toxic for them. Further analysis of TF3 properties revealed that TF3 blocked Hla-prompting immune reaction by inhibiting production and secretion of IL1β, IL6, and TNFα in vitro and in vivo, through affecting NFκB activity. Additionally, we observed that TF3 also markedly attenuated S. aureus-induced barrier disruption, by inhibiting Hla-triggered E-cadherin and ZO-1 impairment. Overall, by blocking activity of Hla, TF3 subsequently subdued the inflammation and protected the epithelial barrier, which is considered as beneficial to relieving skin injury.
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Affiliation(s)
- Anna Goc
- Department of Infectious Diseases, Dr. Rath Research Institute, San Jose, California, United States of America
| | - Waldemar Sumera
- Department of Infectious Diseases, Dr. Rath Research Institute, San Jose, California, United States of America
| | - Matthias Rath
- Department of Infectious Diseases, Dr. Rath Research Institute, San Jose, California, United States of America
| | - Aleksandra Niedzwiecki
- Department of Infectious Diseases, Dr. Rath Research Institute, San Jose, California, United States of America
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12
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Hsieh RC, Liu R, Burgin DJ, Otto M. Understanding mechanisms of virulence in MRSA: implications for antivirulence treatment strategies. Expert Rev Anti Infect Ther 2023; 21:911-928. [PMID: 37501364 DOI: 10.1080/14787210.2023.2242585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/26/2023] [Indexed: 07/29/2023]
Abstract
INTRODUCTION Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen, often causing recurrent and deadly infections in the hospital and community. Many S. aureus virulence factors have been suggested as potential targets for antivirulence therapy to decrease the threat of diminishing antibiotic availability. Antivirulence methods hold promise due to their adjunctive and prophylactic potential and decreased risk for selective pressure. AREAS COVERED This review describes the dominant virulence mechanisms exerted by MRSA and antivirulence therapeutics that are currently undergoing testing in clinical or preclinical stages. We also discuss the advantages and downsides of several investigational antivirulence approaches, including the targeting of bacterial transporters, host-directed therapy, and quorum-sensing inhibitors. For this review, a systematic search of literature on PubMed, Google Scholar, and Web of Science for relevant search terms was performed in April and May 2023. EXPERT OPINION Vaccine and antibody strategies have failed in clinical trials and could benefit from more basic science-informed approaches. Antivirulence-targeting approaches need to be set up better to meet the requirements of drug development, rather than only providing limited results to provide 'proof-of-principle' translational value of pathogenesis research. Nevertheless, there is great potential of such strategies and potential particular promise for novel probiotic approaches.
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Affiliation(s)
- Roger C Hsieh
- Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Ryan Liu
- Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Dylan J Burgin
- Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Michael Otto
- Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Bethesda, Maryland, USA
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13
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Fu T, Fan Z, Li Y, Li Z, Zhao H, Feng Y, Xue G, Cui J, Yan C, Gan L, Feng J, Yuan J, You F. Roles of the Crp/Fnr Family Regulator ArcR in the Hemolysis and Biofilm of Staphylococcus aureus. Microorganisms 2023; 11:1656. [PMID: 37512829 PMCID: PMC10384999 DOI: 10.3390/microorganisms11071656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 07/30/2023] Open
Abstract
Staphylococcus aureus is an opportunistic human pathogen that is often involved in severe infections such as pneumonia and sepsis in which bacterial virulence factors play a key role. Infections caused by S. aureus are often difficult to eradicate, particularly when they are associated with biofilm. The physiological roles of the Crp/Fnr family regulator ArcR are elusive in S. aureus. In this study, it was found that the deletion of arcR increased the hemolytic ability and biofilm formation in S. aureus. Differential gene expression analysis by RNA-seq and real-time quantitative reverse transcription PCR showed that genes associated with hemolytic ability (hla and hlb) and biofilm formation (icaA, icaB, icaC and icaD) were significantly upregulated compared with those in the wild-type strain. The results revealed that ArcR regulated the expression of the hla and ica operon by binding to their promoter regions, respectively. This study provided new insights into the functional importance of ArcR in regulating the virulence and biofilm of S. aureus.
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Affiliation(s)
- Tongtong Fu
- School of Basic Medical Sciences, Peking University, Beijing 100020, China
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Zheng Fan
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Yujie Li
- Department of Life Science and Medicine, University of Science and Technology of China, Hefei 230026, China
| | - Zhoufei Li
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Hanqing Zhao
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Yanling Feng
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Guanhua Xue
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Jinghua Cui
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Chao Yan
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Lin Gan
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Junxia Feng
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Jing Yuan
- Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
| | - Fuping You
- School of Basic Medical Sciences, Peking University, Beijing 100020, China
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14
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Nurxat N, Wang L, Wang Q, Li S, Jin C, Shi Y, Wulamu A, Zhao N, Wang Y, Wang H, Li M, Liu Q. Commensal Staphylococcus epidermidis Defends against Staphylococcus aureus through SaeRS Two-Component System. ACS OMEGA 2023; 8:17712-17718. [PMID: 37251147 PMCID: PMC10210170 DOI: 10.1021/acsomega.3c00263] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/26/2023] [Indexed: 05/31/2023]
Abstract
Staphylococcus aureus is a high-virulent Gram-positive pathogen that is responsible for a serious of diseases. The emergence of antibiotic-resistant S. aureus poses a significant challenge in terms of treatment. The recent research on the human microbiome suggested that the application of commensal bacteria is a new strategy for combating pathogenic infections. Staphylococcus epidermidis, one of the most abundant species in the nasal microbiome, is able to inhibit the colonization of S. aureus. However, during bacterial competition, S. aureus undergoes evolutionary changes to adapt to the diverse environment. Our study has demonstrated that the nasal colonized S. epidermidis possesses the ability to inhibit the hemolytic activity of S. aureus. Moreover, we deciphered another layer of mechanism to inhibit S. aureus colonization by S. epidermidis. The active component present in the cell-free culture of S. epidermidis was found to significantly reduce the hemolytic activity of S. aureus in SaeRS- and Agr-dependent manner. Specifically, the hemolytic inhibition on the S. aureus Agr-I type by S. epidermidis is primarily dependent on the SaeRS two-component system. The active component is characterized as a small molecule that is heat sensitive and protease resistant. Critically, S. epidermidis significantly inhibit the virulence of S. aureus in a mouse skin abscess model, suggesting that the active compound could potentially be used as a therapeutic agent for managing S. aureus infections.
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Affiliation(s)
- Nadira Nurxat
- Department
of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Lili Wang
- Department
of Stomatology, Tongji Hospital, Tongji
University, Shanghai 200065, China
| | - Qichen Wang
- Department
of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Shujing Li
- Faculty
of Medical Laboratory Science, Shanghai
Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, China
| | - Chen Jin
- Faculty
of Medical Laboratory Science, Shanghai
Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, China
| | - Yaran Shi
- Faculty
of Medical Laboratory Science, Shanghai
Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, China
| | - Ayjiamali Wulamu
- Faculty
of Medical Laboratory Science, Shanghai
Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, China
| | - Na Zhao
- Department
of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yanan Wang
- Department
of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Hua Wang
- Department
of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Min Li
- Department
of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Faculty
of Medical Laboratory Science, Shanghai
Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, China
| | - Qian Liu
- Department
of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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15
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Tao Z, Wang H, Ke K, Shi D, Zhu L. Flavone inhibits Staphylococcus aureus virulence via inhibiting the sae two component system. Microb Pathog 2023; 180:106128. [PMID: 37148922 DOI: 10.1016/j.micpath.2023.106128] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/08/2023] [Accepted: 04/26/2023] [Indexed: 05/08/2023]
Abstract
The rising prevalence of antibiotic resistance in Staphylococcus aureus calls for the development of innovative antimicrobial agents targeting novel pathways. S. aureus generates various virulence factors that compromise host defense mechanisms. Flavone, a core structure of flavonoids, has been shown to diminish the production of staphyloxanthin and alpha-hemolysin. Nonetheless, the influence of flavone on the majority of other virulence factors in S. aureus and its underlying molecular mechanism remain elusive. In this study, we examined the impact of flavone on the transcriptional profile of S. aureus using transcriptome sequencing. Our findings revealed that flavone substantially downregulated the expression of over 30 virulence factors implicated in immune evasion by the pathogen. Gene set enrichment analysis of the fold change-ranked gene list in relation to the Sae regulon indicated a robust association between flavone-induced downregulation and membership in the Sae regulon. Through the analysis of Sae target promoter-gfp fusion expression patterns, we observed a dose-dependent inhibition of Sae target promoter activity by flavone. Moreover, we discovered that flavone protected human neutrophils from S. aureus-mediated killing. Flavone also decreased the expression of alpha-hemolysin and other hemolytic toxins, resulting in a reduction in S. aureus' hemolytic capacity. Additionally, our data suggested that the inhibitory effect of flavone on the Sae system operates independently of its capacity to lower staphyloxanthin levels. In conclusion, our study proposes that flavone exhibits a broad inhibitory action on multiple virulence factors of S. aureus by targeting the Sae system, consequently diminishing the bacterium's pathogenicity.
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Affiliation(s)
- Zhanhua Tao
- Institute of Eco-Environmental Research, Guangxi Academy of Sciences, Nanning, 530003, Guangxi, China; Guangxi Key Laboratory of Marine Natural Products and Combinatorial Biosynthesis Chemistry, Nanning, 530003, Guangxi, China.
| | - Haoren Wang
- The First Affiliated Hospital of Jiamusi University, Jiamusi, 154002, Heilongjiang, China.
| | - Ke Ke
- Guangxi Academy of Sciences, Nanning, 530003, Guangxi, China.
| | - Deqiang Shi
- Guangxi Academy of Sciences, Nanning, 530003, Guangxi, China.
| | - Libo Zhu
- Guangxi Academy of Sciences, Nanning, 530003, Guangxi, China.
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16
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Braï MA, Hannachi N, El Gueddari N, Baudoin JP, Dahmani A, Lepidi H, Habib G, Camoin-Jau L. The Role of Platelets in Infective Endocarditis. Int J Mol Sci 2023; 24:ijms24087540. [PMID: 37108707 PMCID: PMC10143005 DOI: 10.3390/ijms24087540] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/02/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
Over the last decade, the incidence of infective endocarditis (IE) has increased, with a change in the frequency of causative bacteria. Early evidence has substantially demonstrated the crucial role of bacterial interaction with human platelets, with no clear mechanistic characterization in the pathogenesis of IE. The pathogenesis of endocarditis is so complex and atypical that it is still unclear how and why certain bacterial species will induce the formation of vegetation. In this review, we will analyze the key role of platelets in the physiopathology of endocarditis and in the formation of vegetation, depending on the bacterial species. We provide a comprehensive outline of the involvement of platelets in the host immune response, investigate the latest developments in platelet therapy, and discuss prospective research avenues for solving the mechanistic enigma of bacteria-platelet interaction for preventive and curative medicine.
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Affiliation(s)
- Mustapha Abdeljalil Braï
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France
| | - Nadji Hannachi
- Laboratoire de Biopharmacie et Pharmacotechnie, Faculté de Médecine, Université Ferhat Abbas Sétif I, Sétif 19000, Algeria
| | - Nabila El Gueddari
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France
- Service de Chirurgie Cardiaque, Hôpital de la Timone, APHM, Boulevard Jean-Moulin, 13385 Marseille, France
| | - Jean-Pierre Baudoin
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France
| | - Abderrhamane Dahmani
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France
| | - Hubert Lepidi
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France
- Service d'Anatomo-Pathologie, Hôpital de la Timone, APHM, Boulevard Jean-Moulin, 13385 Marseille, France
| | - Gilbert Habib
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France
- Service de Cardiologie, Hôpital de la Timone, APHM, Boulevard Jean-Moulin, 13385 Marseille, France
| | - Laurence Camoin-Jau
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France
- Laboratoire d'Hématologie, Hôpital de la Timone, APHM, Boulevard Jean-Moulin, 13385 Marseille, France
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17
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Peng Q, Tang X, Dong W, Sun N, Yuan W. A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism. Antibiotics (Basel) 2022; 12:antibiotics12010012. [PMID: 36671212 PMCID: PMC9854888 DOI: 10.3390/antibiotics12010012] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/23/2022] [Accepted: 11/25/2022] [Indexed: 12/24/2022] Open
Abstract
Bacteria can form biofilms in natural and clinical environments on both biotic and abiotic surfaces. The bacterial aggregates embedded in biofilms are formed by their own produced extracellular matrix. Staphylococcus aureus (S. aureus) is one of the most common pathogens of biofilm infections. The formation of biofilm can protect bacteria from being attacked by the host immune system and antibiotics and thus bacteria can be persistent against external challenges. Therefore, clinical treatments for biofilm infections are currently encountering difficulty. To address this critical challenge, a new and effective treatment method needs to be developed. A comprehensive understanding of bacterial biofilm formation and regulation mechanisms may provide meaningful insights against antibiotic resistance due to bacterial biofilms. In this review, we discuss an overview of S. aureus biofilms including the formation process, structural and functional properties of biofilm matrix, and the mechanism regulating biofilm formation.
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Affiliation(s)
- Qi Peng
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 510180, China
| | - Xiaohua Tang
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 510180, China
| | - Wanyang Dong
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 510180, China
| | - Ning Sun
- Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
- Correspondence: (N.S.); (W.Y.)
| | - Wenchang Yuan
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 510180, China
- Correspondence: (N.S.); (W.Y.)
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18
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Zhao N, Wang Y, Liu J, Yang Z, Jian Y, Wang H, Ahmed M, Li M, Bae T, Liu Q. Molybdopterin biosynthesis pathway contributes to the regulation of SaeRS two-component system by ClpP in Staphylococcus aureus. Virulence 2022; 13:727-739. [PMID: 35481455 PMCID: PMC9067530 DOI: 10.1080/21505594.2022.2065961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 03/06/2022] [Accepted: 04/11/2022] [Indexed: 11/09/2022] Open
Abstract
In Staphylococcus aureus, the SaeRS two-component system is essential for the bacterium's hemolytic activity and virulence. The Newman strain of S. aureus contains a variant of SaeS sensor kinase, SaeS L18P. Previously, we showed that, in the strain Newman, SaeS L18P is degraded by the membrane-bound protease FtsH. Intriguingly, the knockout mutation of clpP, encoding the cytoplasmic protease ClpP, greatly reduces the expression of SaeS L18P. Here, we report that, in the strain Newman, the positive regulatory role of ClpP on the SaeS L18P expression is due to its destabilizing effect on FtsH and degradation of MoeA, a molybdopterin biosynthesis protein. Although the transcription of ftsH was not affected by ClpP, the expression level of FtsH was increased in the clpP mutant. The destabilizing effect appears to be indirect because ClpXP did not directly degrade FtsH in an in vitro assay. Through transposon mutagenesis, we found out that the moeA gene, encoding the molybdopterin biosynthesis protein A, suppresses the hemolytic activity of S. aureus along with the transcription and expression of SaeS L18P. In a proteolysis assay, ClpXP directly degraded MoeA, demonstrating that MoeA is a substrate of the protease. In a murine bloodstream infection model, the moeA mutant displayed reduced virulence and lower survival compared with the WT strain. Based on these results, we concluded that ClpP positively controls the expression of SaeS L18P in an FtsH and MoeA-dependent manner, and the physiological role of MoeA outweighs its suppressive effect on the SaeRS TCS during infection.
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Affiliation(s)
- Na Zhao
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yanan Wang
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Junlan Liu
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ziyu Yang
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Jian
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hua Wang
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mahmoud Ahmed
- Department of Biology, Indiana University Northwest, Gary, IN, USA
| | - Min Li
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Taeok Bae
- Department of Microbiology and Immunology, Indiana University School of Medicine-Northwest, Gary, IN, USA
| | - Qian Liu
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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19
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Zhang W, Ran J, Shang L, Zhang L, Wang M, Fei C, Chen C, Gu F, Liu Y. Niclosamide as a repurposing drug against Gram-positive bacterial infections. J Antimicrob Chemother 2022; 77:3312-3320. [PMID: 36173387 DOI: 10.1093/jac/dkac319] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/30/2022] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Niclosamide is commonly used as an antiparasitic drug in veterinary clinics. The objectives of this study were to evaluate the efficacy of niclosamide against resistant Gram-positive bacteria in vitro and in an in vivo experimental model of topical bacterial infection. Moreover, to study the antibacterial mechanism of niclosamide to Staphylococcus aureus. METHODS A mouse topical infection model was established to detect the antibacterial activity of niclosamide in vivo. The antimicrobial mechanism was probed by visualizing the bacterial morphologies using scanning electron microscopy and transmission electron microscopy. Moreover, the haemolytic assay and western blotting analysis were performed to evaluate whether niclosamide could inhibit the secretion of alpha-haemolysin (α-HL) from S. aureus. RESULTS The MICs of niclosamide were below 0.5 mg/L for Gram-positive bacteria, showing excellent antibacterial activity in vitro. The in vivo antibacterial activity results indicated that niclosamide treatment at 10 mg/kg of body weight caused a significant reduction in the abscess area and the number of S. aureus cells. Moreover, the antibacterial mechanism of niclosamide showed that the surface morphology of S. aureus displayed noticeable shrinkage, with an increasing number of small vacuole-like structures observed as the drug concentration increased. Intracellular ATP levels were found to decrease in a niclosamide dose-dependent manner. Haemolysis and western blotting analyses revealed that niclosamide inhibited the haemolytic activity of S. aureus by inhibiting α-HL expression under subinhibitory concentration conditions. CONCLUSIONS Niclosamide has significant potential for development into drugs that prevent and treat diseases caused by Gram-positive bacteria such as Staphylococcus and Streptococcus.
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Affiliation(s)
- Wei Zhang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
| | - Jinxin Ran
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
| | - Lu Shang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
| | - Lifang Zhang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
| | - Mi Wang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
| | - Chenzhong Fei
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
| | - Chan Chen
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
| | - Feng Gu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
| | - Yingchun Liu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.,Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai 200241, China
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20
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Cengher L, Manna AC, Cho J, Theprungsirikul J, Sessions K, Rigby W, Cheung AL. Regulation of neutrophil myeloperoxidase inhibitor SPIN by the small RNA Teg49 in Staphylococcus aureus. Mol Microbiol 2022; 117:1447-1463. [PMID: 35578788 PMCID: PMC9880452 DOI: 10.1111/mmi.14919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/04/2022] [Accepted: 05/11/2022] [Indexed: 01/31/2023]
Abstract
Teg49 is a Staphylococcus aureus trans-acting regulatory sRNA derived from cleavage of the sarA P3 transcript. We showed by RNA-Seq here that the 5' trident-like structure in Teg49 regulates transcriptionally (direct and indirect) 22 genes distinct from sarA. Among these, Teg49 was noted to repress spn, encoding a 102 residue preprotein which yields the mature 73 residue peptide which inhibits the catalytic activity of myeloperoxidase in human neutrophils. Teg49 was found to regulate spn mRNA post-transcriptionally in strain SH1000 through 9-nt base-pairing between hairpin loop 2 of Teg49 and an exposed bulge of the spn mRNA. Mutations of the Teg49 binding site disrupted the repression of spn, leading to reduced degradation, and increased half-life of spn mRNA in the Teg49 mutant. The spn-Teg49 interaction was also confirmed with a synonymous spn mutation to yield enhanced spn expression in the mutant vs. the parent. The Teg49 mutant with increased spn expression exhibited enhanced resistance to MPO activity in vitro. Killing assays with human neutrophils showed that the Teg49 mutant was more resistant to killing after phagocytosis. Altogether, this study shows that Teg49 in S. aureus has a distinct and important regulatory profile whereby this sRNA modulates resistance to myeloperoxidase-mediated killing by human neutrophils.
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Affiliation(s)
- Liviu Cengher
- Department of Microbiology and Immunology, Geisel School of Medicine Dartmouth College Hanover New Hampshire USA
| | - Adhar C. Manna
- Department of Microbiology and Immunology, Geisel School of Medicine Dartmouth College Hanover New Hampshire USA
| | - Junho Cho
- Department of Microbiology and Immunology, Geisel School of Medicine Dartmouth College Hanover New Hampshire USA
| | - Jomkuan Theprungsirikul
- Department of Microbiology and Immunology, Geisel School of Medicine Dartmouth College Hanover New Hampshire USA
| | - Katherine Sessions
- Department of Microbiology and Immunology, Geisel School of Medicine Dartmouth College Hanover New Hampshire USA
| | - William Rigby
- Department of Microbiology and Immunology, Geisel School of Medicine Dartmouth College Hanover New Hampshire USA
| | - Ambrose L. Cheung
- Department of Microbiology and Immunology, Geisel School of Medicine Dartmouth College Hanover New Hampshire USA
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21
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Fernandez JS, Tuttobene MR, Montaña S, Subils T, Cantera V, Iriarte A, Tuchscherr L, Ramirez MS. Staphylococcus aureus α-Toxin Effect on Acinetobacter baumannii Behavior. BIOLOGY 2022; 11:biology11040570. [PMID: 35453769 PMCID: PMC9028598 DOI: 10.3390/biology11040570] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/02/2022] [Accepted: 04/06/2022] [Indexed: 11/16/2022]
Abstract
Polymicrobial infections are more challenging to treat and are recognized as responsible for significant morbidity and mortality. It has been demonstrated that multiple Gram-negative organisms take advantage of the effects of Staphylococcus aureus α-toxin on mucosal host defense, resulting in proliferation and dissemination of the co-infecting pathogens. Through phenotypic approaches, we observed a decrease in the motility of A. baumannii A118 after exposure to cell-free conditioned media (CFCM) of S. aureus strains, USA300 and LS1. However, the motility of A. baumannii A118 was increased after exposure to the CFCM of S. aureus strains USA300 Δhla and S. aureus LSI ΔagrA. Hemolytic activity was seen in A118, in the presence of CFCM of S. aureus LS1. Further, A. baumannii A118 showed an increase in biofilm formation and antibiotic resistance to tetracycline, in the presence of CFCM of S. aureus USA300. Transcriptomic analysis of A. baumannii A118, with the addition of CFCM from S. aureus USA300, was carried out to study A. baumannii response to S. aureus’ released molecules. The RNA-seq data analysis showed a total of 463 differentially expressed genes, associated with a wide variety of functions, such as biofilm formation, virulence, and antibiotic susceptibility, among others. The present results showed that A. baumannii can sense and respond to molecules secreted by S. aureus. These findings demonstrate that A. baumannii may perceive and respond to changes in its environment; specifically, when in the presence of CFCM from S. aureus.
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Affiliation(s)
- Jennifer S. Fernandez
- Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USA; (J.S.F.); (M.R.T.)
| | - Marisel R. Tuttobene
- Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USA; (J.S.F.); (M.R.T.)
- Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET), Rosario S2000, Argentina
| | - Sabrina Montaña
- Laboratorio de Bacteriología Clínica, Departamento de Bioquímica Clínica, Hospital de Clínicas José de San Martín, Facultad de Farmacia y Bioquímica, Buenos Aires C1113, Argentina;
| | - Tomás Subils
- Instituto de Procesos Biotecnológicos y Químicos de Rosario (IPROBYQ, CONICET-UNR), Rosario S2000, Argentina;
| | - Virginia Cantera
- Laboratorio de Biología Computacional, Departamento de Desarrollo Biotecnológico, Facultad de Medicina, Universidad de la República, Montevideo 11200, Uruguay; (V.C.); (A.I.)
| | - Andrés Iriarte
- Laboratorio de Biología Computacional, Departamento de Desarrollo Biotecnológico, Facultad de Medicina, Universidad de la República, Montevideo 11200, Uruguay; (V.C.); (A.I.)
| | - Lorena Tuchscherr
- Institute of Medical Microbiology, Jena University Hospital, 07747 Jena, Germany;
| | - Maria Soledad Ramirez
- Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USA; (J.S.F.); (M.R.T.)
- Correspondence: ; Tel.: +1-657-278-4562
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22
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Gao K, Su B, Dai J, Li P, Wang R, Yang X. Anti-Biofilm and Anti-Hemolysis Activities of 10-Hydroxy-2-decenoic Acid against Staphylococcus aureus. Molecules 2022; 27:1485. [PMID: 35268586 PMCID: PMC8912057 DOI: 10.3390/molecules27051485] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 12/03/2022] Open
Abstract
Persistent infections caused by Staphylococcus aureus biofilms pose a major threat to global public health. 10-Hydroxy-2-decenoic acid (10-HDA), a main fatty acid in royal jelly, has been shown to possess various biological activities. The purpose of this study was to explore the effects of 10-HDA on the biofilms and virulence of S. aureus and its potential molecular mechanism. Quantitative crystal violet staining indicated that 10-HDA significantly reduced the biofilm biomass at sub-minimum inhibitory concentration (MIC) levels (1/32MIC to 1/2MIC). Scanning electron microscope (SEM) observations demonstrated that 10-HDA inhibited the secretion of extracellular polymeric substances, decreased bacterial adhesion and aggregation, and disrupted biofilm architecture. Moreover, 10-HDA could significantly decrease the biofilm viability and effectively eradicated the mature biofilms. It was also found that the hemolytic activity of S. aureus was significantly inhibited by 10-HDA. qRT-PCR analyses revealed that the expressions of global regulators sarA, agrA, and α-hemolysin gene hla were downregulated by 10-HDA. These results indicate that 10-HDA could be used as a potential natural antimicrobial agent to control the biofilm formation and virulence of S. aureus.
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Affiliation(s)
- Kuankuan Gao
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China; (K.G.); (B.S.); (P.L.); (R.W.)
- Key Laboratory of Shandong Microbial Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;
| | - Bei Su
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China; (K.G.); (B.S.); (P.L.); (R.W.)
- Key Laboratory of Shandong Microbial Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;
| | - Jing Dai
- Key Laboratory of Shandong Microbial Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;
| | - Piwu Li
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China; (K.G.); (B.S.); (P.L.); (R.W.)
- Key Laboratory of Shandong Microbial Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;
| | - Ruiming Wang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China; (K.G.); (B.S.); (P.L.); (R.W.)
- Key Laboratory of Shandong Microbial Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;
| | - Xiaohui Yang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China; (K.G.); (B.S.); (P.L.); (R.W.)
- Key Laboratory of Shandong Microbial Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;
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23
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Guo H, Tong Y, Cheng J, Abbas Z, Li Z, Wang J, Zhou Y, Si D, Zhang R. Biofilm and Small Colony Variants-An Update on Staphylococcus aureus Strategies toward Drug Resistance. Int J Mol Sci 2022; 23:ijms23031241. [PMID: 35163165 PMCID: PMC8835882 DOI: 10.3390/ijms23031241] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/16/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Recently, the drawbacks arising from the overuse of antibiotics have drawn growing public attention. Among them, drug-resistance (DR) and even multidrug-resistance (MDR) pose significant challenges in clinical practice. As a representative of a DR or MDR pathogen, Staphylococcus aureus can cause diversity of infections related to different organs, and can survive or adapt to the diverse hostile environments by switching into other phenotypes, including biofilm and small colony variants (SCVs), with altered physiologic or metabolic characteristics. In this review, we briefly describe the development of the DR/MDR as well as the classical mechanisms (accumulation of the resistant genes). Moreover, we use multidimensional scaling analysis to evaluate the MDR relevant hotspots in the recent published reports. Furthermore, we mainly focus on the possible non-classical resistance mechanisms triggered by the two important alternative phenotypes of the S. aureus, biofilm and SCVs, which are fundamentally caused by the different global regulation of the S. aureus population, such as the main quorum-sensing (QS) and agr system and its coordinated regulated factors, such as the SarA family proteins and the alternative sigma factor σB (SigB). Both the biofilm and the SCVs are able to escape from the host immune response, and resist the therapeutic effects of antibiotics through the physical or the biological barriers, and become less sensitive to some antibiotics by the dormant state with the limited metabolisms.
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24
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Schwarz C, Töre Y, Hoesker V, Ameling S, Grün K, Völker U, Schulze PC, Franz M, Faber C, Schaumburg F, Niemann S, Hoerr V. Host-pathogen interactions of clinical S. aureus isolates to induce infective endocarditis. Virulence 2021; 12:2073-2087. [PMID: 34490828 PMCID: PMC8425731 DOI: 10.1080/21505594.2021.1960107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
To evaluate potential pathomechanisms in the induction of infective endocarditis (IE), 34 Staphylococcus aureus (S. aureus) isolates, collected from patients with S. aureus endocarditis and from healthy individuals were investigated both in vitro and in vivo. S. aureus isolates were tested in vitro for their cytotoxicity, invasion and the association with platelets. Virulence factor expression profiles and cellular response were additionally investigated and tested for correlation with the ability of S. aureus to induce vegetations on the aortic valves in vivo. In an animal model of IE valvular conspicuity was assessed by in vivo magnetic resonance imaging at 9.4 T, histology and enrichment gene expression analysis. All S. aureus isolates tested in vivo caused a reliable infection and inflammation of the aortic valves, but could not be differentiated and categorized according to the measured in vitro virulence profiles and cytotoxicity. Results from in vitro assays did not correlate with the severity of IE. However, the isolates differed substantially in the activation and inhibition of pathways connected to the extracellular matrix and inflammatory response. Thus, comprehensive approaches of host-pathogen interactions and corresponding immune pathways are needed for the evaluation of the pathogenic capacity of bacteria. An improved understanding of the interaction between virulence factors and immune response in S. aureus infective endocarditis would offer novel possibilities for the development of therapeutic strategies and specific diagnostic imaging markers.
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Affiliation(s)
- Christian Schwarz
- Translational Research Imaging Center, Clinic for Radiology, University Hospital Muenster, Muenster, Germany
| | - Yasemin Töre
- Translational Research Imaging Center, Clinic for Radiology, University Hospital Muenster, Muenster, Germany
| | - Vanessa Hoesker
- Translational Research Imaging Center, Clinic for Radiology, University Hospital Muenster, Muenster, Germany
| | - Sabine Ameling
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | - Katja Grün
- Department of Internal Medicine I, Jena University Hospital, Jena, Germany
| | - Uwe Völker
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | | | - Marcus Franz
- Department of Internal Medicine I, Jena University Hospital, Jena, Germany
| | - Cornelius Faber
- Translational Research Imaging Center, Clinic for Radiology, University Hospital Muenster, Muenster, Germany
| | - Frieder Schaumburg
- Institute of Medical Microbiology, University Hospital Muenster, Muenster, Germany
| | - Silke Niemann
- Institute of Medical Microbiology, University Hospital Muenster, Muenster, Germany
| | - Verena Hoerr
- Translational Research Imaging Center, Clinic for Radiology, University Hospital Muenster, Muenster, Germany.,Institute of Medical Microbiology, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany.,Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany
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25
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Dhungel L, Burcham L, Park JY, Sampathkumar HD, Cudjoe A, Seo KS, Jordan H. Responses to chemical cross-talk between the Mycobacterium ulcerans toxin, mycolactone, and Staphylococcus aureus. Sci Rep 2021; 11:11746. [PMID: 34083568 PMCID: PMC8175560 DOI: 10.1038/s41598-021-89177-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/22/2021] [Indexed: 02/01/2023] Open
Abstract
Buruli ulcer is a neglected tropical disease caused by the environmental pathogen, Mycobacterium ulcerans whose major virulence factor is mycolactone, a lipid cytotoxic molecule. Buruli ulcer has high morbidity, particularly in rural West Africa where the disease is endemic. Data have shown that infected lesions of Buruli ulcer patients can be colonized by quorum sensing bacteria such as Staphylococcus aureus, S. epidermidis, and Pseudomonas aeruginosa, but without typical pathology associated with those pathogens' colonization. M. ulcerans pathogenesis may not only be an individual act but may also be dependent on synergistic or antagonistic mechanisms within a polymicrobial network. Furthermore, co-colonization by these pathogens may promote delayed wound healing, especially after the initiation of antibiotic therapy. Hence, it is important to understand the interaction of M. ulcerans with other bacteria encountered during skin infection. We added mycolactone to S. aureus and incubated for 3, 6 and 24 h. At each timepoint, S. aureus growth and hemolytic activity was measured, and RNA was isolated to measure virulence gene expression through qPCR and RNASeq analyses. Results showed that mycolactone reduced S. aureus hemolytic activity, suppressed hla promoter activity, and attenuated virulence genes, but did not affect S. aureus growth. RNASeq data showed mycolactone greatly impacted S. aureus metabolism. These data are relevant and significant as mycolactone and S. aureus sensing and response at the transcriptional, translational and regulation levels will provide insight into biological mechanisms of interspecific interactions that may play a role in regulation of responses such as effects between M. ulcerans, mycolactone, and S. aureus virulence that will be useful for treatment and prevention.
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Affiliation(s)
- Laxmi Dhungel
- Department of Biological Sciences, Mississippi State University, P.O. Box GY, Starkville, MS, 39762, USA
| | - Lindsey Burcham
- Department of Biological Sciences, Mississippi State University, P.O. Box GY, Starkville, MS, 39762, USA
| | - Joo Youn Park
- Department of Biological Sciences, Mississippi State University, P.O. Box GY, Starkville, MS, 39762, USA
| | - Harshini Devi Sampathkumar
- Department of Biological Sciences, Mississippi State University, P.O. Box GY, Starkville, MS, 39762, USA
| | | | - Keun Seok Seo
- Department of Biological Sciences, Mississippi State University, P.O. Box GY, Starkville, MS, 39762, USA
| | - Heather Jordan
- Department of Biological Sciences, Mississippi State University, P.O. Box GY, Starkville, MS, 39762, USA.
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26
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Schilcher K, Horswill AR. Staphylococcal Biofilm Development: Structure, Regulation, and Treatment Strategies. Microbiol Mol Biol Rev 2020; 84:e00026-19. [PMID: 32792334 PMCID: PMC7430342 DOI: 10.1128/mmbr.00026-19] [Citation(s) in RCA: 380] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In many natural and clinical settings, bacteria are associated with some type of biotic or abiotic surface that enables them to form biofilms, a multicellular lifestyle with bacteria embedded in an extracellular matrix. Staphylococcus aureus and Staphylococcus epidermidis, the most frequent causes of biofilm-associated infections on indwelling medical devices, can switch between an existence as single free-floating cells and multicellular biofilms. During biofilm formation, cells first attach to a surface and then multiply to form microcolonies. They subsequently produce the extracellular matrix, a hallmark of biofilm formation, which consists of polysaccharides, proteins, and extracellular DNA. After biofilm maturation into three-dimensional structures, the biofilm community undergoes a disassembly process that leads to the dissemination of staphylococcal cells. As biofilms are dynamic and complex biological systems, staphylococci have evolved a vast network of regulatory mechanisms to modify and fine-tune biofilm development upon changes in environmental conditions. Thus, biofilm formation is used as a strategy for survival and persistence in the human host and can serve as a reservoir for spreading to new infection sites. Moreover, staphylococcal biofilms provide enhanced resilience toward antibiotics and the immune response and impose remarkable therapeutic challenges in clinics worldwide. This review provides an overview and an updated perspective on staphylococcal biofilms, describing the characteristic features of biofilm formation, the structural and functional properties of the biofilm matrix, and the most important mechanisms involved in the regulation of staphylococcal biofilm formation. Finally, we highlight promising strategies and technologies, including multitargeted or combinational therapies, to eradicate staphylococcal biofilms.
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Affiliation(s)
- Katrin Schilcher
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alexander R Horswill
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
- Department of Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, USA
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27
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Schilcher K, Horswill AR. Staphylococcal Biofilm Development: Structure, Regulation, and Treatment Strategies. Microbiol Mol Biol Rev 2020. [PMID: 32792334 DOI: 10.1128/mmbr.00026-19/asset/e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2023] Open
Abstract
In many natural and clinical settings, bacteria are associated with some type of biotic or abiotic surface that enables them to form biofilms, a multicellular lifestyle with bacteria embedded in an extracellular matrix. Staphylococcus aureus and Staphylococcus epidermidis, the most frequent causes of biofilm-associated infections on indwelling medical devices, can switch between an existence as single free-floating cells and multicellular biofilms. During biofilm formation, cells first attach to a surface and then multiply to form microcolonies. They subsequently produce the extracellular matrix, a hallmark of biofilm formation, which consists of polysaccharides, proteins, and extracellular DNA. After biofilm maturation into three-dimensional structures, the biofilm community undergoes a disassembly process that leads to the dissemination of staphylococcal cells. As biofilms are dynamic and complex biological systems, staphylococci have evolved a vast network of regulatory mechanisms to modify and fine-tune biofilm development upon changes in environmental conditions. Thus, biofilm formation is used as a strategy for survival and persistence in the human host and can serve as a reservoir for spreading to new infection sites. Moreover, staphylococcal biofilms provide enhanced resilience toward antibiotics and the immune response and impose remarkable therapeutic challenges in clinics worldwide. This review provides an overview and an updated perspective on staphylococcal biofilms, describing the characteristic features of biofilm formation, the structural and functional properties of the biofilm matrix, and the most important mechanisms involved in the regulation of staphylococcal biofilm formation. Finally, we highlight promising strategies and technologies, including multitargeted or combinational therapies, to eradicate staphylococcal biofilms.
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Affiliation(s)
- Katrin Schilcher
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alexander R Horswill
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
- Department of Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, USA
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28
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Kong R, Lee YS, Kang DH, Wang S, Li Q, Kwon DY, Kang OH. The antibacterial activity and toxin production control of bee venom in mouse MRSA pneumonia model. BMC Complement Med Ther 2020; 20:238. [PMID: 32718325 PMCID: PMC7385961 DOI: 10.1186/s12906-020-02991-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/16/2020] [Indexed: 01/02/2023] Open
Abstract
Background The current antimicrobial therapy is still important for the treatment of pneumonia due to MRSA infection, but there are some limitations, including the route of administration, side effect profile, and increased microbial resistance patterns. Therefore, we investigated whether BV, which shows a strong antimicrobial effect against MRSA, would be effective in a pneumonia model. Methods In vitro, we checked MIC, qRT-PCR, western blot, ELISA, LDH-assay. In vivo, we checked survival rate, gross pathological change, histopathology, lung bacterial clearance assay, and the expression of inflammatory related gene. Results The minimum inhibitory concentration of BV against MRSA is 15.6 μg/ml by broth dilution method. The production of toxins and related gene were reduced by BV in MRSA. The secretion of cytokines were decreased by treatment with BV in 264.7 RAW macrophages stimulated by MRSA Also, BV protected A549 from pathogenicity of MRSA. Bee venom reduced the number of bacteria in the lungs and alleviated the symptoms of MRSA-induced pneumonia in mouse. Conclusion BV inhibited the virulence of the bacterium and the number of bacterial cells present in lung tissue, thereby alleviating the symptoms of pneumonia in mice. This study suggested that BV may be a candidate substance for the treatment of pneumonia caused by MRSA infection.
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Affiliation(s)
- Ryong Kong
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Young-Seob Lee
- Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, RDA, 92 Bisanro, Eumsung, Chungbuk, 27709, Republic of Korea
| | - Dam-Hee Kang
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Shu Wang
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Qianqian Li
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Dong-Yeul Kwon
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Ok-Hwa Kang
- Department of Oriental Pharmacy, College of Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea.
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29
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Virulence factors and clonal diversity of Staphylococcus aureus in colonization and wound infection with emphasis on diabetic foot infection. Eur J Clin Microbiol Infect Dis 2020; 39:2235-2246. [PMID: 32683595 PMCID: PMC7669779 DOI: 10.1007/s10096-020-03984-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/03/2020] [Indexed: 12/12/2022]
Abstract
Foot ulcer is a common complication in diabetic subjects and infection of these wounds contributes to increased rates of morbidity and mortality. Diabetic foot infections are caused by a multitude of microbes and Staphylococcus aureus, a major nosocomial and community-associated pathogen, significantly contributes to wound infections as well. Staphylococcus aureus is also the primary pathogen commonly associated with diabetic foot osteomyelitis and can cause chronic and recurrent bone infections. The virulence capability of the pathogen and host immune factors can determine the occurrence and progression of S. aureus infection. Pathogen-related factors include complexity of bacterial structure and functional characteristics that provide metabolic and adhesive properties to overcome host immune response. Even though, virulence markers and toxins of S. aureus are broadly similar in different wound models, certain distinguishing features can be observed in diabetic foot infection. Specific clonal lineages and virulence factors such as TSST-1, leukocidins, enterotoxins, and exfoliatins play a significant role in determining wound outcomes. In this review, we describe the role of specific virulence determinants and clonal lineages of S. aureus that influence wound colonization and infection with special reference to diabetic foot infections.
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30
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El-Mowafy M, Elgaml A, Shaaban M. New Approaches for Competing Microbial Resistance and Virulence. Microorganisms 2020. [DOI: 10.5772/intechopen.90388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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31
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Li L, Wang G, Li Y, Francois P, Bayer AS, Chen L, Seidl K, Cheung A, Xiong YQ. Impact of the Novel Prophage ϕSA169 on Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection. mSystems 2020; 5:e00178-20. [PMID: 32606024 PMCID: PMC7329321 DOI: 10.1128/msystems.00178-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 06/16/2020] [Indexed: 12/26/2022] Open
Abstract
Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections are life-threatening syndromes with few therapeutic options. The potential impact of bacteriophages on the persistent outcome has not been well studied. In this study, we investigated the role of a novel prophage (ϕSA169) in MRSA persistence by using a lysogen-free clinically resolving bacteremia (RB) isolate and comparing it to a derivative which was obtained by infecting the RB strain with ϕSA169, which has been lysogenized in a clinical persistent MRSA bacteremia (PB) isolate. Similar to the PB isolate, the ϕSA169-lysogenized RB strain exhibited well-defined in vitro and in vivo phenotypic and genotypic signatures related to the persistent outcome, including earlier activation of global regulators (i.e., sigB, sarA, agr RNAIII, and sae); higher expression of a critical purine biosynthesis gene, purF; and higher growth rates accompanied by lower ATP levels and vancomycin (VAN) susceptibility and stronger δ-hemolysin and biofilm formation versus its isogenic parental RB isolate. Notably, the contribution of ϕSA169 in persistent outcome with VAN treatment was confirmed in an experimental infective endocarditis model. Taken together, these results indicate the critical role of the prophage ϕSA169 in persistent MRSA endovascular infections. Further studies are needed to identify the mechanisms of ϕSA169 in mediating the persistence, as well as establishing the scope of impact, of this prophage in other PB strains.IMPORTANCE Bacteriophages are viruses that invade the bacterial host, disrupt bacterial metabolism, and cause the bacterium to lyse. Because of its remarkable antibacterial activity and unique advantages over antibiotics, for instance, bacteriophage is specific for one species of bacteria and resistance to phage is less common than resistance to antibiotics. Indeed, bacteriophage therapy for treating infections due to multidrug-resistant pathogens in humans has become a research hot spot. However, it is also worth considering that bacteriophages are transferable and could cotransfer host chromosomal genes, e.g., virulence and antimicrobial resistance genes, while lysogenizing and integrating into the bacterial chromosome (prophage), thus playing a role in bacterial evolution and virulence. In the current study, we identified a novel prophage, ϕSA169, from a clinical persistent MRSA bacteremia isolate, and we determined that ϕSA169 mediated well-defined in vitro and in vivo phenotypic and genotypic signatures related to the persistent outcome, which may represent a unique and important persistent mechanism(s).
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Affiliation(s)
- Liang Li
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Genzhu Wang
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Yi Li
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | | | - Arnold S Bayer
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
- David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- Department of Medicine, Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Liang Chen
- Center for Discovery and Innovation, Nutley, New Jersey, USA
| | - Kati Seidl
- University Hospital of Zurich, Zurich, Switzerland
| | | | - Yan Q Xiong
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
- David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- Department of Medicine, Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California, USA
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De Gregorio E, Esposito A, Vollaro A, De Fenza M, D’Alonzo D, Migliaccio A, Iula VD, Zarrilli R, Guaragna A. N-Nonyloxypentyl-l-Deoxynojirimycin Inhibits Growth, Biofilm Formation and Virulence Factors Expression of Staphylococcus aureus. Antibiotics (Basel) 2020; 9:E362. [PMID: 32604791 PMCID: PMC7344813 DOI: 10.3390/antibiotics9060362] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/15/2020] [Accepted: 06/24/2020] [Indexed: 12/14/2022] Open
Abstract
Staphylococcus aureus is one of the major causes of hospital- and community-associated bacterial infections throughout the world, which are difficult to treat due to the rising number of drug-resistant strains. New molecules displaying potent activity against this bacterium are urgently needed. In this study, d- and l-deoxynojirimycin (DNJ) and a small library of their N-alkyl derivatives were screened against S. aureus ATCC 29213, with the aim to identify novel candidates with inhibitory potential. Among them, N-nonyloxypentyl-l-DNJ (l-NPDNJ) proved to be the most active compound against S. aureus ATCC 29213 and its clinical isolates, with the minimum inhibitory concentration (MIC) value of 128 μg/mL. l-NPDNJ also displayed an additive effect with gentamicin and oxacillin against the gentamicin- and methicillin-resistant S. aureus isolate 00717. Sub-MIC values of l-NPDNJ affected S. aureus biofilm development in a dose-dependent manner, inducing a strong reduction in biofilm biomass. Moreover, real-time reverse transcriptase PCR analysis revealed that l-NPDNJ effectively inhibited at sub-MIC values the transcription of the spa, hla, hlb and sea virulence genes, as well as the agrA and saeR response regulator genes.
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Affiliation(s)
- Eliana De Gregorio
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy;
| | - Anna Esposito
- Department of Chemical Sciences, University of Naples Federico II, Via Cintia, 80126 Naples, Italy; (A.E.); (M.D.F.); (D.D.)
| | - Adriana Vollaro
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy;
| | - Maria De Fenza
- Department of Chemical Sciences, University of Naples Federico II, Via Cintia, 80126 Naples, Italy; (A.E.); (M.D.F.); (D.D.)
| | - Daniele D’Alonzo
- Department of Chemical Sciences, University of Naples Federico II, Via Cintia, 80126 Naples, Italy; (A.E.); (M.D.F.); (D.D.)
| | - Antonella Migliaccio
- Department of Public Health, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (A.M.); (R.Z.)
| | - Vita Dora Iula
- Complex Operative Unit of Clinical Pathology, “Ospedale del Mare-ASL NA1 Centro”, 80131 Naples, Italy;
| | - Raffaele Zarrilli
- Department of Public Health, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (A.M.); (R.Z.)
| | - Annalisa Guaragna
- Department of Chemical Sciences, University of Naples Federico II, Via Cintia, 80126 Naples, Italy; (A.E.); (M.D.F.); (D.D.)
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Li L, Wang G, Cheung A, Abdelhady W, Seidl K, Xiong YQ. MgrA Governs Adherence, Host Cell Interaction, and Virulence in a Murine Model of Bacteremia Due to Staphylococcus aureus. J Infect Dis 2020; 220:1019-1028. [PMID: 31177268 DOI: 10.1093/infdis/jiz219] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 04/26/2019] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND MgrA is an important global virulence gene regulator in Staphylococcus aureus. In the present study, the role of mgrA in host-pathogen interactions related to virulence was explored in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains. METHODS In vitro susceptibilities to human defense peptides (HDPs), adherence to fibronectin (Fn) and endothelial cells (ECs), EC damage, α-toxin production, expression of global regulator (eg, agr RNAIII) and its downstream effectors (eg, α-toxin [hla] and Fn binding protein A [fnbA]), MgrA binding to fnbA promoter, and the effect on HDP-induced mprF and dltA expression were analyzed. The impact of mgrA on virulence was evaluated using a mouse bacteremia model. RESULTS mgrA mutants displayed significantly higher susceptibility to HDPs, which might be related to the decreased HDP-induced mprF and dltA expression but decreased Fn and EC adherence, EC damage, α-toxin production, agr RNAIII, hla and fnbA expression, and attenuated virulence in the bacteremia model as compared to their respective parental and mgrA-complemented strains. Importantly, direct binding of MgrA to the fnbA promoter was observed. CONCLUSIONS These results suggest that mgrA mediates host-pathogen interactions and virulence and may provide a novel therapeutic target for invasive S. aureus infections.
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Affiliation(s)
- Liang Li
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance
| | - Genzhu Wang
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance
| | | | - Wessam Abdelhady
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance
| | - Kati Seidl
- University Hospital of Zurich, Switzerland
| | - Yan Q Xiong
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance.,David Geffen School of Medicine at UCLA, Los Angeles, California
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Vollaro A, Esposito A, Antonaki E, Iula VD, D’Alonzo D, Guaragna A, De Gregorio E. Steroid Derivatives as Potential Antimicrobial Agents Against Staphylococcus aureus Planktonic Cells. Microorganisms 2020; 8:E468. [PMID: 32218320 PMCID: PMC7232480 DOI: 10.3390/microorganisms8040468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/22/2020] [Accepted: 03/23/2020] [Indexed: 12/28/2022] Open
Abstract
In this work, the antibacterial activity of deflazacort and several of its synthetic precursors was tested against a panel of bacterial pathogens responsible for most drug-resistant infections including Staphylococcus aureus, Enterococcus spp., Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. The derivative of deflazacort, PYED-1 (pregnadiene-11-hydroxy-16α,17α-epoxy-3,20-dione-1) showed the best antibacterial activity in a dose-dependent way. We focused on the action of PYED-1 against S. aureus cells. PYED-1 exhibited an additive antimicrobial effect with gentamicin and oxacillin against the methicillin-resistant S. aureus isolate 00717. In addition to its antimicrobial effect, PYED-1 was found to repress the expression of several virulence factors of S. aureus, including toxins encoded by the hla (alpha-haemolysin), hlb (beta-haemolysin), lukE-D (leucotoxins E-D), and sea (staphylococcal enterotoxin A) genes, and cell surface factors (fnbB (fibronectin-binding protein B) and capC (capsule biosynthesis protein C)). The expression levels of autolysin isaA (immunodominant staphylococcal antigen) were also increased.
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Affiliation(s)
- Adriana Vollaro
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (A.V.); (E.A.)
| | - Anna Esposito
- Department of Chemical Sciences, University of Naples Federico II, Via Cintia, 80126 Naples, Italy; (A.E.); (D.D.)
| | - Eleni Antonaki
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (A.V.); (E.A.)
| | - Vita Dora Iula
- Complex Operative Unit of Clinical Pathology, “Ospedale del Mare-ASL NA1 Centro”, 80147 Naples, Italy;
| | - Daniele D’Alonzo
- Department of Chemical Sciences, University of Naples Federico II, Via Cintia, 80126 Naples, Italy; (A.E.); (D.D.)
| | - Annalisa Guaragna
- Department of Chemical Sciences, University of Naples Federico II, Via Cintia, 80126 Naples, Italy; (A.E.); (D.D.)
| | - Eliana De Gregorio
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (A.V.); (E.A.)
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Marchetti M, De Bei O, Bettati S, Campanini B, Kovachka S, Gianquinto E, Spyrakis F, Ronda L. Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development. Int J Mol Sci 2020; 21:E2145. [PMID: 32245010 PMCID: PMC7139808 DOI: 10.3390/ijms21062145] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/16/2020] [Accepted: 03/17/2020] [Indexed: 02/08/2023] Open
Abstract
Nutritional immunity is a form of innate immunity widespread in both vertebrates and invertebrates. The term refers to a rich repertoire of mechanisms set up by the host to inhibit bacterial proliferation by sequestering trace minerals (mainly iron, but also zinc and manganese). This strategy, selected by evolution, represents an effective front-line defense against pathogens and has thus inspired the exploitation of iron restriction in the development of innovative antimicrobials or enhancers of antimicrobial therapy. This review focuses on the mechanisms of nutritional immunity, the strategies adopted by opportunistic human pathogen Staphylococcus aureus to circumvent it, and the impact of deletion mutants on the fitness, infectivity, and persistence inside the host. This information finally converges in an overview of the current development of inhibitors targeting the different stages of iron uptake, an as-yet unexploited target in the field of antistaphylococcal drug discovery.
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Affiliation(s)
- Marialaura Marchetti
- Interdepartmental Center Biopharmanet-TEC, University of Parma, 43124 Parma, Italy; (M.M.); (S.B.)
| | - Omar De Bei
- Department of Food and Drug, University of Parma, 43124 Parma, Italy; (O.D.B.); (B.C.)
| | - Stefano Bettati
- Interdepartmental Center Biopharmanet-TEC, University of Parma, 43124 Parma, Italy; (M.M.); (S.B.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- Institute of Biophysics, National Research Council, 56124 Pisa, Italy
- National Institute of Biostructures and Biosystems, 00136 Rome, Italy
| | - Barbara Campanini
- Department of Food and Drug, University of Parma, 43124 Parma, Italy; (O.D.B.); (B.C.)
| | - Sandra Kovachka
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (S.K.); (E.G.); (F.S.)
| | - Eleonora Gianquinto
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (S.K.); (E.G.); (F.S.)
| | - Francesca Spyrakis
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (S.K.); (E.G.); (F.S.)
| | - Luca Ronda
- Interdepartmental Center Biopharmanet-TEC, University of Parma, 43124 Parma, Italy; (M.M.); (S.B.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- Institute of Biophysics, National Research Council, 56124 Pisa, Italy
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Abstract
The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in Staphylococcus aureus. A primary function of the extracellular proteases of Staphylococcus aureus is to control the progression of infection by selectively modulating the stability of virulence factors. Consequently, a regulatory network exists to titrate protease abundance/activity to influence the accumulation, or lack thereof, of individual virulence factors. Herein, we comprehensively map this system, exploring the regulation of the four protease loci by known and novel factors. In so doing, we determined that seven major elements (SarS, SarR, Rot, MgrA, CodY, SaeR, and SarA) form the primary network of control, with the latter three being the most powerful. We note that expression of aureolysin is largely repressed by these factors, while the spl operon is subject to the strongest upregulation of any protease loci, particularly by SarR and SaeR. Furthermore, when exploring scpA expression, we find it to be profoundly influenced in opposing fashions by SarA (repressor) and SarR (activator). We also present the screening of >100 regulator mutants of S. aureus, identifying 7 additional factors (ArgR2, AtlR, MntR, Rex, XdrA, Rbf, and SarU) that form a secondary circuit of protease control. Primarily, these elements serve as activators, although we reveal XdrA as a new repressor of protease expression. With the exception or ArgR2, each of the new effectors appears to work through the primary network of regulation to influence protease production. Collectively, we present a comprehensive regulatory circuit that emphasizes the complexity of protease regulation and suggest that its existence speaks to the importance of these enzymes to S. aureus physiology and pathogenic potential. IMPORTANCE The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in Staphylococcus aureus.
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Singh V, Phukan UJ. Interaction of host and Staphylococcus aureus protease-system regulates virulence and pathogenicity. Med Microbiol Immunol 2019; 208:585-607. [PMID: 30483863 DOI: 10.1007/s00430-018-0573-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 11/22/2018] [Indexed: 02/06/2023]
Abstract
Staphylococcus aureus causes various health care- and community-associated infections as well as certain chronic TH2 driven inflammatory diseases. It is a potent pathogen with serious virulence and associated high morbidity. Severe pathogenicity is accredited to the S. aureus secreted virulence factors such as proteases and host protease modulators. These virulence factors promote adhesion and invasion of bacteria through damage of tight junction barrier and keratinocytes. They inhibit activation and transmigration of various immune cells such as neutrophils (and neutrophil proteases) to evade opsono-phagocytosis and intracellular bacterial killing. Additionally, they protect the bacteria from extracellular killing by disrupting integrity of extracellular matrix. Platelet activation and agglutination is also impaired by these factors. They also block the classical as well as alternative pathways of complement activation and assist in spread of infection through blood and tissue. As these factors are exquisite factors of S. aureus mediated disease development, we have focused on review of diversification of various protease-system associated virulence factors, their structural building, diverse role in disease development and available therapeutic counter measures. This review summarises the role of protease-associated virulence factors during invasion and progression of disease.
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Affiliation(s)
- Vigyasa Singh
- Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, India
| | - Ujjal Jyoti Phukan
- School of Life Science, Jawaharlal Nehru University, New Delhi, 110067, India.
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Gudeta DD, Lei MG, Lee CY. Contribution of hla Regulation by SaeR to Staphylococcus aureus USA300 Pathogenesis. Infect Immun 2019; 87:e00231-19. [PMID: 31209148 PMCID: PMC6704604 DOI: 10.1128/iai.00231-19] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 06/11/2019] [Indexed: 02/08/2023] Open
Abstract
The SaeRS two-component system in Staphylococcus aureus is critical for regulation of many virulence genes, including hla, which encodes alpha-toxin. However, the impact of regulation of alpha-toxin by Sae on S. aureus pathogenesis has not been directly addressed. Here, we mutated the SaeR-binding sequences in the hla regulatory region and determined the contribution of this mutation to hla expression and pathogenesis in strain USA300 JE2. Western blot analyses revealed drastic reduction of alpha-toxin levels in the culture supernatants of SaeR-binding mutant in contrast to the marked alpha-toxin production in the wild type. The SaeR-binding mutation had no significant effect on alpha-toxin regulation by Agr, MgrA, and CcpA. In animal studies, we found that the SaeR-binding mutation did not contribute to USA300 JE2 pathogenesis using a rat infective endocarditis model. However, in a rat skin and soft tissue infection model, the abscesses on rats infected with the mutant were significantly smaller than the abscesses on those infected with the wild type but similar to the abscesses on those infected with a saeR mutant. These studies indicated that there is a direct effect of hla regulation by SaeR on pathogenesis but that the effect depends on the animal model used.
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Affiliation(s)
- Dereje D Gudeta
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Mei G Lei
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Chia Y Lee
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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Zhang H, Jiang JM, Han L, Lao YZ, Zheng D, Chen YY, Wan SJ, Zheng CW, Tan HS, Li ZG, Xu HX. Uncariitannin, a polyphenolic polymer from Uncaria gambier, attenuates Staphylococcus aureus virulence through an MgrA-mediated regulation of α-hemolysin. Pharmacol Res 2019; 147:104328. [PMID: 31288080 DOI: 10.1016/j.phrs.2019.104328] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 06/20/2019] [Accepted: 06/21/2019] [Indexed: 10/26/2022]
Abstract
A global transcriptional regulator, MgrA, was previously identified as a key determinant of virulence in Staphylococcus aureus. An 80% EtOH extract of Uncaria gambier was found to attenuate the virulence of S. aureus via its effects on MgrA. Using bioassay-guided fractionation, a polyphenolic polymer, uncariitannin, was found to be the main bioactive constituent of the extract, and its structure was characterized using spectral and chemical analysis. The molecular weight and polydispersity of uncariitannin were determined by gel permeation chromatography-refractive index-light scattering analysis. An electrophoretic mobility shift assay showed that uncariitannin could effectively inhibit the interaction of MgrA with DNA in a dose-dependent manner. Treatment with uncariitannin could decrease the mRNA and protein levels of Hla in both the S. aureus Newman and USA300 LAC strains. Further analysis of Hla expression levels in the Newman ΔmgrA and Newman ΔmgrA/pYJ335-mgrA strains indicated that uncariitannin altered Hla expression primarily in an MgrA-dependent manner. A mouse model of infection indicated that uncariitannin could attenuate MRSA virulence. In conclusion, uncariitannin may be a potential candidate for further development as an antivirulence agent for the treatment of S. aureus infection.
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Affiliation(s)
- Hong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Jia-Ming Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Li Han
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Yuan-Zhi Lao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Dan Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Yu-Yu Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Shi-Jie Wan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Chang-Wu Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Hong-Sheng Tan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Zi-Gang Li
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, PR China.
| | - Hong-Xi Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Centre of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China.
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Staphylococcus aureus Toxins: From Their Pathogenic Roles to Anti-virulence Therapy Using Natural Products. BIOTECHNOL BIOPROC E 2019. [DOI: 10.1007/s12257-019-0059-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Astley R, Miller FC, Mursalin MH, Coburn PS, Callegan MC. An Eye on Staphylococcus aureus Toxins: Roles in Ocular Damage and Inflammation. Toxins (Basel) 2019; 11:E356. [PMID: 31248125 PMCID: PMC6628431 DOI: 10.3390/toxins11060356] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 06/13/2019] [Accepted: 06/15/2019] [Indexed: 12/12/2022] Open
Abstract
Staphylococcus aureus (S. aureus) is a common pathogen of the eye, capable of infecting external tissues such as the tear duct, conjunctiva, and the cornea, as well the inner and more delicate anterior and posterior chambers. S. aureus produces numerous toxins and enzymes capable of causing profound damage to tissues and organs, as well as modulating the immune response to these infections. Unfortunately, in the context of ocular infections, this can mean blindness for the patient. The role of α-toxin in corneal infection (keratitis) and infection of the interior of the eye (endophthalmitis) has been well established by comparing virulence in animal models and α-toxin-deficient isogenic mutants with their wild-type parental strains. The importance of other toxins, such as β-toxin, γ-toxin, and Panton-Valentine leukocidin (PVL), have been analyzed to a lesser degree and their roles in eye infections are less clear. Other toxins such as the phenol-soluble modulins have yet to be examined in any animal models for their contributions to virulence in eye infections. This review discusses the state of current knowledge of the roles of S. aureus toxins in eye infections and the controversies existing as a result of the use of different infection models. The strengths and limitations of these ocular infection models are discussed, as well as the need for physiological relevance in the study of staphylococcal toxins in these models.
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Affiliation(s)
- Roger Astley
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Frederick C Miller
- Department of Cell Biology and Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Md Huzzatul Mursalin
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Phillip S Coburn
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Michelle C Callegan
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
- Dean McGee Eye Institute, 608 Stanton L. Young Blvd., DMEI PA-418, Oklahoma City, OK 73104, USA.
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Candida albicans Augments Staphylococcus aureus Virulence by Engaging the Staphylococcal agr Quorum Sensing System. mBio 2019; 10:mBio.00910-19. [PMID: 31164467 PMCID: PMC6550526 DOI: 10.1128/mbio.00910-19] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Relatively little is known about the complex interactions and signaling events that occur between microbes and even less so about how microbial “cross talk” shapes human health and disease. Candida albicans (a fungus) and Staphylococcus aureus (a bacterium) are formidable human nosocomial pathogens, causing severe morbidity and mortality. Moreover, they are frequently coisolated from central venous catheters and deep-seated infections, including intra-abdominal sepsis. In this work, we have shown that coinfection with C. albicans and S. aureus is highly lethal, leading to >80% mortality by day 1 postinfection, whereas monoinfection with C. albicans or S. aureus does not cause mortality. This infectious synergism is dependent on the expression of staphylococcal alpha-toxin, and secretion of this potent virulence factor is actually augmented by C. albicans via an agr-dependent mechanism. Moreover, prophylactic neutralization of alpha-toxin with a monoclonal antibody is sufficient to elicit protection during coinfection. Therefore, we have demonstrated that a pathogenic fungus can enhance virulence determinants of a bacterium in vivo with devastating consequences to the host. These results have important implications in the surveillance and treatment of polymicrobial disease and highlight the dynamic intersection of environment, pathogens, and host. Candida albicans and Staphylococcus aureus are among the most prevalent nosocomial pathogens that are responsible for severe morbidity and mortality, even with appropriate treatment. Using a murine model of polymicrobial intra-abdominal infection (IAI), we have previously shown that coinfection with these pathogens results in synergistic lethality that is partially dependent on exacerbated prostaglandin signaling, while monomicrobial infection is nonlethal. Therefore, the objective of this study was to identify staphylococcal virulence determinants that drive lethal synergism during polymicrobial IAI. Using the toxigenic S. aureus strain JE2, we observed that coinfection with C. albicans led to a striking 80 to 100% mortality rate within 20 h postinoculation (p.i.) while monomicrobial infections were nonlethal. Use of a green fluorescent protein (GFP)-P3 promoter S. aureus reporter strain revealed enhanced activation of the staphylococcal agr quorum sensing system during in vitro polymicrobial versus monomicrobial growth. Analyses by quantitative real-time PCR (qPCR), Western blot, and toxin functional assays confirmed enhanced agr-associated gene transcription and increases in secreted alpha- and delta-toxins. C. albicans-mediated elevated toxin production and hemolytic activity were determined to be agrA dependent, and genetic knockout and complementation of hla identified alpha-toxin as the key staphylococcal virulence factor driving lethal synergism. Analysis of mono- and polymicrobial infections 8 h p.i. demonstrated equivalent bacterial burdens in the peritoneal cavity but significantly elevated levels of alpha-toxin (3-fold) and the eicosanoid prostaglandin E2 (PGE2) (4-fold) during coinfection. Importantly, prophylactic passive immunization using the monoclonal anti-alpha-toxin antibody MEDI4893* led to significantly improved survival rates compared to those following treatment with isotype control antibody. Collectively, these results define alpha-toxin as an essential virulence determinant during C. albicans-S. aureus IAI and describe a novel mechanism by which a human-pathogenic fungus can augment the virulence of a highly pathogenic bacterium in vivo.
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43
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Phenotypic and Genotypic Characteristics of Methicillin-Resistant Staphylococcus aureus (MRSA) Related to Persistent Endovascular Infection. Antibiotics (Basel) 2019; 8:antibiotics8020071. [PMID: 31146412 PMCID: PMC6627527 DOI: 10.3390/antibiotics8020071] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 05/22/2019] [Accepted: 05/24/2019] [Indexed: 12/03/2022] Open
Abstract
Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (PB) represents an important subset of S. aureus infection and correlates with poor clinical outcomes. MRSA isolates from patients with PB differ significantly from those of resolving bacteremia (RB) with regard to several in vitro phenotypic and genotypic profiles. For instance, PB strains exhibit less susceptibility to cationic host defense peptides and vancomycin (VAN) killing under in vivo-like conditions, greater damage to endothelial cells, thicker biofilm formation, altered growth rates, early activation of many global virulence regulons (e.g., sigB, sarA, sae and agr) and higher expression of purine biosynthesis genes (e.g., purF) than RB strains. Importantly, PB strains are significantly more resistant to VAN treatment in experimental infective endocarditis as compared to RB strains, despite similar VAN minimum inhibitory concentrations (MICs) in vitro. Here, we review relevant phenotypic and genotypic characteristics related to the PB outcome. These and future insights may improve our understanding of the specific mechanism(s) contributing to the PB outcome, and aid in the development of novel therapeutic and preventative measures against this life-threatening infection.
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44
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Chen L, Zhang X, Peng X, Yang Y, Yu H. Baicalin tetrazole acts as anti-pneumocystis carinii pneumonia candidate in immunosuppressed rat model. Microb Pathog 2019; 132:59-65. [PMID: 31002962 DOI: 10.1016/j.micpath.2019.04.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/05/2019] [Accepted: 04/15/2019] [Indexed: 10/27/2022]
Abstract
The present study was aimed to synthesize and evaluate tetrazoles of baicalin against Pneumocystis carinii pneumonia in the rat model. Among the seven synthesized baicalin tetrazoles, one with trifloromethyl group in the aromatic ring was found to be most potent during the initial study. The mechanism of preventive effect of most potent compound 4c against Pneumocystis carinii pneumonia was investigated in detail. The compound 4c decreased the parasitic load by almost 99% in the rats. It significantly (P < 0.05) decreased mortality rate of the rats, prevented pulmonary tissue damage and aggregation of inflammatory cytokines. In Pneumocystis carinii infected rats compound 4c treatment inhibited production of interleukin-18, interleukin-1β and TNF-α significantly (P < 0.05) in the BALF and pulmonary tissues. Treatment of the pneumocystis carinii-infected rats with compound 4c inhibited up-regulation of mRNA expression corresponding NLRP3, ASC and caspase-1. The compound 4c treatment of the pneumocystis carinii-infected rats significantly (P < 0.02) suppressed the level of NLRP3 and ASC proteins. Moreover, the enhancement of caspase-1 activation by pneumocystis carinii-infection in rats was also suppressed by compound 4c. The results from present study demonstrate that compound 4c protects pneumocystis carinii induced pneumonia through suppression of inflammatory cytokines and NLRP3 activation. Therefore, compound 4c can be of therapeutic importance for the treatment of pneumocystis carinii induced pneumonia.
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Affiliation(s)
- Lin Chen
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Xin Zhang
- Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Xiaying Peng
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yang Yang
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Hua Yu
- Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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Fleitas Martínez O, Cardoso MH, Ribeiro SM, Franco OL. Recent Advances in Anti-virulence Therapeutic Strategies With a Focus on Dismantling Bacterial Membrane Microdomains, Toxin Neutralization, Quorum-Sensing Interference and Biofilm Inhibition. Front Cell Infect Microbiol 2019; 9:74. [PMID: 31001485 PMCID: PMC6454102 DOI: 10.3389/fcimb.2019.00074] [Citation(s) in RCA: 176] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 03/05/2019] [Indexed: 12/11/2022] Open
Abstract
Antimicrobial resistance constitutes one of the major challenges facing humanity in the Twenty-First century. The spread of resistant pathogens has been such that the possibility of returning to a pre-antibiotic era is real. In this scenario, innovative therapeutic strategies must be employed to restrict resistance. Among the innovative proposed strategies, anti-virulence therapy has been envisioned as a promising alternative for effective control of the emergence and spread of resistant pathogens. This review presents some of the anti-virulence strategies that are currently being developed, it will cover strategies focused on quench pathogen quorum sensing (QS) systems, disassemble of bacterial functional membrane microdomains (FMMs), disruption of biofilm formation and bacterial toxin neutralization.
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Affiliation(s)
- Osmel Fleitas Martínez
- Programa de Pós-Graduação em Patologia Molecular, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil.,Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Centro de Análises Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brasília, Brazil
| | - Marlon Henrique Cardoso
- Programa de Pós-Graduação em Patologia Molecular, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil.,Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Centro de Análises Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brasília, Brazil.,S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil
| | - Suzana Meira Ribeiro
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados, Brazil
| | - Octavio Luiz Franco
- Programa de Pós-Graduação em Patologia Molecular, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil.,Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Centro de Análises Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brasília, Brazil.,S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil
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46
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Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence. Nat Commun 2019; 10:775. [PMID: 30770821 PMCID: PMC6377658 DOI: 10.1038/s41467-019-08724-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 01/18/2019] [Indexed: 11/09/2022] Open
Abstract
Staphylococcus aureus is a significant cause of human infection. Here, we demonstrate that mutations in the transcriptional repressor of purine biosynthesis, purR, enhance the pathogenic potential of S. aureus. Indeed, systemic infection with purR mutants causes accelerated mortality in mice, which is due to aberrant up-regulation of fibronectin binding proteins (FnBPs). Remarkably, purR mutations can arise upon exposure of S. aureus to stress, such as an intact immune system. In humans, naturally occurring anti-FnBP antibodies exist that, while not protective against recurrent S. aureus infection, ostensibly protect against hypervirulent S. aureus infections. Vaccination studies support this notion, where anti-Fnb antibodies in mice protect against purR hypervirulence. These findings provide a novel link between purine metabolism and virulence in S. aureus.
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47
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Dweba CC, Zishiri OT, El Zowalaty ME. Methicillin-resistant Staphylococcus aureus: livestock-associated, antimicrobial, and heavy metal resistance. Infect Drug Resist 2018; 11:2497-2509. [PMID: 30555249 PMCID: PMC6278885 DOI: 10.2147/idr.s175967] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Staphylococcus aureus is an opportunistic pathogen of human and other mammals that is of increasing clinical and veterinary importance due to its ability to rapidly develop antimicrobial resistance. The injudicious use of antibiotics has given rise to the emergence of antibiotic resistant S. aureus strains, most importantly methicillin-resistant Staphylococcus aureus (MRSA). The emergence of livestock-associated MRSA (LA-MRSA) has highlighted the importance of directed research toward its prevention, as well as the need for the discovery and development of more efficient treatment than is currently available. Furthermore, the treatment of MRSA is complicated by the co-selection of heavy metal and antibiotic resistance genes by microorganisms. Livestock and livestock production systems are large reservoirs of heavy metals due to their use in feed as well as environmental contaminant, which has allowed for the selection of LA-MRSA isolates with heavy metal resistance. The World Health Organization reported that Africa has the largest gaps in data on the prevalence of antimicrobial resistance, with no reports on rates for LA-MRSA harboring heavy metal resistance in South Africa. This review aimed to report the emergence of LA-MRSA in South Africa, specifically the most frequent sequence type ST398, globally. Furthermore, we aimed to highlight the importance of LA-MRSA in clinical and food security, as well as this research gap in South Africa. This review sheds light on the prevalence of heavy metals in livestock farms and abattoirs, and focuses on the phenomenon of the co-selection of heavy metal and antibiotic resistance genes in MRSA, emphasizing the importance of a focused direction for research in humans, animals as well as environment using one-health approach.
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Affiliation(s)
- Cwengile C Dweba
- Discipline of Genetics, School of Life Sciences, College of Agriculture Engineering and Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Oliver T Zishiri
- Discipline of Genetics, School of Life Sciences, College of Agriculture Engineering and Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Mohamed E El Zowalaty
- Microbiology and Virology Research Group, School of Health Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa,
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48
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Horn J, Klepsch M, Manger M, Wolz C, Rudel T, Fraunholz M. Long Noncoding RNA SSR42 Controls Staphylococcus aureus Alpha-Toxin Transcription in Response to Environmental Stimuli. J Bacteriol 2018; 200:e00252-18. [PMID: 30150231 PMCID: PMC6199474 DOI: 10.1128/jb.00252-18] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 08/22/2018] [Indexed: 02/02/2023] Open
Abstract
Staphylococcus aureus is a human pathogen causing a variety of diseases by versatile expression of a large set of virulence factors that most prominently features the cytotoxic and hemolytic pore-forming alpha-toxin. Expression of alpha-toxin is regulated by an intricate network of transcription factors. These include two-component systems sensing quorum and environmental signals as well as regulators reacting to the nutritional status of the pathogen. We previously identified the repressor of surface proteins (Rsp) as a virulence regulator. Acute cytotoxicity and hemolysis are strongly decreased in rsp mutants, which are characterized by decreased transcription of toxin genes as well as loss of transcription of a 1,232-nucleotide (nt)-long noncoding RNA (ncRNA), SSR42. Here, we show that SSR42 is the effector of Rsp in transcription regulation of the alpha-toxin gene, hla SSR42 transcription is enhanced after exposure of S. aureus to subinhibitory concentrations of oxacillin which thus leads to an SSR42-dependent increase in hemolysis. Aside from Rsp, SSR42 transcription is under the control of additional global regulators, such as CodY, AgrA, CcpE, and σB, but is positioned upstream of the two-component system SaeRS in the regulatory cascade leading to alpha-toxin production. Thus, alpha-toxin expression depends on two long ncRNAs, SSR42 and RNAIII, which control production of the cytolytic toxin on the transcriptional and translational levels, respectively, with SSR42 as an important regulator of SaeRS-dependent S. aureus toxin production in response to environmental and metabolic signals.IMPORTANCEStaphylococcus aureus is a major cause of life-threatening infections. The bacterium expresses alpha-toxin, a hemolysin and cytotoxin responsible for many of the pathologies of S. aureus Alpha-toxin production is enhanced by subinhibitory concentrations of antibiotics. Here, we show that this process is dependent on the long noncoding RNA, SSR42. Further, SSR42 itself is regulated by several global regulators, thereby integrating environmental and nutritional signals that modulate hemolysis of the pathogen.
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Affiliation(s)
- Jessica Horn
- Biocenter, Chair of Microbiology, University of Würzburg, Würzburg, Germany
| | - Maximilian Klepsch
- Biocenter, Chair of Microbiology, University of Würzburg, Würzburg, Germany
| | - Michelle Manger
- Biocenter, Chair of Microbiology, University of Würzburg, Würzburg, Germany
| | - Christiane Wolz
- Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany
| | - Thomas Rudel
- Biocenter, Chair of Microbiology, University of Würzburg, Würzburg, Germany
- Helmholtz Institute for RNA-based Infection Research (HIRI), Würzburg, Germany
| | - Martin Fraunholz
- Biocenter, Chair of Microbiology, University of Würzburg, Würzburg, Germany
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49
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Li L, Abdelhady W, Donegan NP, Seidl K, Cheung A, Zhou YF, Yeaman MR, Bayer AS, Xiong YQ. Role of Purine Biosynthesis in Persistent Methicillin-Resistant Staphylococcus aureus Infection. J Infect Dis 2018; 218:1367-1377. [PMID: 29868791 PMCID: PMC6151072 DOI: 10.1093/infdis/jiy340] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 06/01/2018] [Indexed: 11/13/2022] Open
Abstract
Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (PB) represents an important subset of S. aureus endovascular infections. In this study, we investigated potential genetic mechanisms underlying the persistent outcomes. Compared with resolving bacteremia (RB) isolates (defined as isolates associated with negative results of blood cultures 2-4 days after initiation of therapy), PB strains (defined as isolates associated with positive results of blood cultures ≥7 days after initiation of therapy) had significantly earlier onset activation of key virulence regulons and structural genes (eg, sigB, sarA, sae, and cap5), higher expression of purine biosynthesis genes (eg, purF), and faster growth rates, with earlier entrance into stationary phase. Importantly, an isogenic strain set featuring a wild-type MRSA isolate, a purF mutant strain, and a purF-complemented strain and use of strategic purine biosynthesis inhibitors implicated a causal relationship between purine biosynthesis and the in vivo persistent outcomes. These observations suggest that purine biosynthesis plays a key role in the outcome of PB and may represent a new target for enhanced efficacy in treating life-threatening MRSA infections.
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Affiliation(s)
- Liang Li
- Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance
| | - Wessam Abdelhady
- Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance
| | | | - Kati Seidl
- University Hospital of Zurich, Switzerland
| | | | - Yu-Feng Zhou
- Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance
- South China Agricultural University, Guangzhou
| | - Michael R Yeaman
- Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance
- David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Arnold S Bayer
- Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance
- David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Yan Q Xiong
- Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance
- David Geffen School of Medicine at UCLA, Los Angeles, California
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50
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Venkatasubramaniam A, Kanipakala T, Ganjbaksh N, Mehr R, Mukherjee I, Krishnan S, Bae T, Aman MJ, Adhikari RP. A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System. Toxins (Basel) 2018; 10:E377. [PMID: 30231498 PMCID: PMC6162840 DOI: 10.3390/toxins10090377] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 09/11/2018] [Accepted: 09/11/2018] [Indexed: 12/18/2022] Open
Abstract
Cytolytic pore-forming toxins including alpha hemolysin (Hla) and bicomponent leukotoxins play an important role in the pathogenesis of Staphylococcus aureus. These toxins kill the polymorphonuclear phagocytes (PMNs), disrupt epithelial and endothelial barriers, and lyse erythrocytes to provide iron for bacterial growth. The expression of these toxins is regulated by the two-component sensing systems Sae and Agr. Here, we report that a point mutation (L18P) in SaeS, the histidine kinase sensor of the Sae system, renders the S. aureus Newman hemolytic activity fully independent of Hla and drastically increases the PMN lytic activity. Furthermore, this Hla-independent activity, unlike Hla itself, can lyse human erythrocytes. The Hla-independent activity towards human erythrocytes was also evident in USA300, however, under strict agr control. Gene knockout studies revealed that this Hla-independent Sae-regulated activity was entirely dependent on gamma hemolysin A subunit (HlgA). In contrast, hemolytic activity of Newman towards human erythrocytes from HlgAB resistant donors was completely dependent on agr. The culture supernatant from Newman S. aureus could be neutralized by antisera against two vaccine candidates based on LukS and LukF subunits of Panton-Valentine leukocidin but not by an anti-Hla neutralizing antibody. These findings display the complex involvement of Sae and Agr systems in regulating the virulence of S. aureus and have important implications for vaccine and immunotherapeutics development for S. aureus disease in humans.
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Affiliation(s)
| | | | | | - Rana Mehr
- Integrated Biotherapeutics Inc., Rockville, MD 20850, USA.
| | | | | | - Taeok Bae
- Department of Microbiology and Immunology, Indiana University School of Medicine-Northwest, Gary, IN 46408, USA.
| | - M Javad Aman
- Integrated Biotherapeutics Inc., Rockville, MD 20850, USA.
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