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1
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Outeda-García M, Garcia-Pose A, Guijarro-Sánchez P, Rodríguez-Coello A, Báez-Barroso GA, Maceiras R, Alonso-García I, Arca-Suárez J, Vázquez-Ucha JC, Bou G, Beceiro A. The novel polymyxin analogue SPR206 exhibits higher activity than colistin against both colistin-susceptible and colistin-resistant strains of Acinetobacter baumannii. Antimicrob Agents Chemother 2025:e0194024. [PMID: 40391936 DOI: 10.1128/aac.01940-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 04/16/2025] [Indexed: 05/22/2025] Open
Abstract
Colistin resistance is increasing globally and complicates treatments of A. baumannii infections. The next-generation polymyxin SPR206 shows potent activity against multidrug-resistant Gram-negative pathogens with low toxicity. SPR206 exhibited higher activity against colistin-susceptible and colistin-resistant strains (MIC50/MIC90 = 0.12/0.25 mg/L), and resistance was only detected in 1/118 strains (MIC ≥4 mg/L). Mutations in pmrCAB, linked to colistin resistance, do not seem to confer resistance to the novel polymyxin, which retains a high level of activity.
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Affiliation(s)
- Michelle Outeda-García
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
| | - Andrea Garcia-Pose
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
| | - Paula Guijarro-Sánchez
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
| | - Arianna Rodríguez-Coello
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
| | - Gabriela Alejandra Báez-Barroso
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
| | - Romina Maceiras
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
| | - Isaac Alonso-García
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
| | - Jorge Arca-Suárez
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto Salud Carlos III, Madrid, Spain
| | - Juan C Vázquez-Ucha
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto Salud Carlos III, Madrid, Spain
| | - German Bou
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto Salud Carlos III, Madrid, Spain
- Department of Physiotherapy, Medicine and Biomedical Sciences, University of A Coruña, A Coruña, Spain
| | - Alejandro Beceiro
- Microbiology Service and Institute for Biomedical Research A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto Salud Carlos III, Madrid, Spain
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2
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De Sousa T, Wang HY, Lin TW, Caniça M, Ramos MJN, Santos D, Silva C, Saraiva S, Beyrouthy R, Bonnet R, Hébraud M, Igrejas G, Poeta P. Mutational Analysis of Colistin-Resistant Pseudomonas aeruginosa Isolates: From Genomic Background to Antibiotic Resistance. Pathogens 2025; 14:387. [PMID: 40333140 PMCID: PMC12030098 DOI: 10.3390/pathogens14040387] [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: 03/17/2025] [Revised: 04/04/2025] [Accepted: 04/09/2025] [Indexed: 05/09/2025] Open
Abstract
This study analyzed eleven isolates of colistin-resistant Pseudomonas aeruginosa, originating from Portugal and Taiwan, which are associated with various pathologies. The results revealed significant genetic diversity among the isolates, with each exhibiting a distinct genetic profile. A prevalence of sequence type ST235 was observed, characterizing it as a high-risk clone, and serotyping indicated a predominance of type O11, associated with chronic respiratory infections in cystic fibrosis (CF) patients. The phylogenetic analysis demonstrated genetic diversity among the isolates, with distinct clades and complex evolutionary relationships. Additionally, transposable elements such as Tn3 and IS6 were identified in all isolates, highlighting their importance in the mobility of antibiotic resistance genes. An analysis of antimicrobial resistance profiles revealed pan-drug resistance in all isolates, with a high prevalence of genes conferring resistance to β-lactams and aminoglycosides. Furthermore, additional analyses revealed mutations in regulatory networks and specific loci previously implicated in colistin resistance, such as pmrA, cprS, phoO, and others, suggesting a possible contribution to the observed resistant phenotype. This study has a strong impact because it not only reveals the genetic diversity and resistance mechanisms in P. aeruginosa but also identifies mutations in regulatory genes associated with colistin resistance.
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Affiliation(s)
- Telma De Sousa
- MicroART—Antibiotic Resistance Team, Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (T.D.S.); (C.S.); (S.S.)
- Department of Genetics and Biotechnology, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal;
- Functional Genomics and Proteomics Unit, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Associated Laboratory for Green Chemistry, University NOVA of Lisbon, 1099-085 Caparica, Portugal
| | - Hsin-Yao Wang
- Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; (H.-Y.W.); (T.-W.L.)
- School of Medicine, National Tsing Hua University, Hsinchu 300, Taiwan
| | - Ting-Wei Lin
- Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; (H.-Y.W.); (T.-W.L.)
| | - Manuela Caniça
- National Reference Laboratory of Antibiotic Resistance and Healthcare Associated Infections, Department of Infectious Diseases, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal; (M.C.); (M.J.N.R.); (D.S.)
- Centre for the Studies of Animal Science (CECA), Institute of Agrarian and Agri-Food Sciences and Technologies, University of Porto, 4099-002 Porto, Portugal
| | - Miguel J. N. Ramos
- National Reference Laboratory of Antibiotic Resistance and Healthcare Associated Infections, Department of Infectious Diseases, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal; (M.C.); (M.J.N.R.); (D.S.)
| | - Daniela Santos
- National Reference Laboratory of Antibiotic Resistance and Healthcare Associated Infections, Department of Infectious Diseases, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal; (M.C.); (M.J.N.R.); (D.S.)
| | - Catarina Silva
- MicroART—Antibiotic Resistance Team, Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (T.D.S.); (C.S.); (S.S.)
| | - Sónia Saraiva
- MicroART—Antibiotic Resistance Team, Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (T.D.S.); (C.S.); (S.S.)
- CECAV—Veterinary and Animal Research Centre, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Racha Beyrouthy
- Institut National de la Santé et de la Recherche Médicale, (UMR1071), Institute National de la Recherche Agronomique (USC-2018), Université Clermont Auvergne, 63000 Clermont-Ferrand, France; (R.B.); (R.B.)
- Centre National de Référence de la Résistance aux Antibiotiques, Centre Hospitalier Universitaire, 63000 Clermont-Ferrand, France
| | - Richard Bonnet
- Institut National de la Santé et de la Recherche Médicale, (UMR1071), Institute National de la Recherche Agronomique (USC-2018), Université Clermont Auvergne, 63000 Clermont-Ferrand, France; (R.B.); (R.B.)
- Centre National de Référence de la Résistance aux Antibiotiques, Centre Hospitalier Universitaire, 63000 Clermont-Ferrand, France
| | - Michel Hébraud
- INRAE, Université Clermont Auvergne, UMR Microbiologie Environnement Digestif Santé (MEDiS), 63122 Saint-Genès-Champanelle, France;
| | - Gilberto Igrejas
- Department of Genetics and Biotechnology, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal;
- Functional Genomics and Proteomics Unit, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Associated Laboratory for Green Chemistry, University NOVA of Lisbon, 1099-085 Caparica, Portugal
| | - Patrícia Poeta
- MicroART—Antibiotic Resistance Team, Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal; (T.D.S.); (C.S.); (S.S.)
- Associated Laboratory for Green Chemistry, University NOVA of Lisbon, 1099-085 Caparica, Portugal
- CECAV—Veterinary and Animal Research Centre, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Veterinary and Animal Research Centre, Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
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3
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Hondros AD, Young MM, Jaimes FE, Kinkead J, Thompson RJ, Melander C, Cavanagh J. Two-Component System Sensor Kinase Inhibitors Target the ATP-Lid of PmrB to Disrupt Colistin Resistance in Acinetobacter baumannii. Biochemistry 2025; 64:1317-1327. [PMID: 40056100 DOI: 10.1021/acs.biochem.4c00789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Two-component systems serve as ubiquitous communication modules that enable bacteria to detect and respond to various stimuli by regulating cellular processes such as growth, viability, and, most notably, antimicrobial resistance. Classical two-component systems consist of two proteins: an initial membrane-bound sensor histidine kinase and a DNA-binding response regulator that induces the appropriate response within the cell. Numerous studies have implicated the PmrAB two-component system in facilitating resistance to the last-resort antibiotic polymyxin E (colistin) in Acinetobacter baumannii. As initiators of the signaling pathways that elicit resistance, histidine kinases present ideal targets for developing antibiotic adjuvant drugs. Despite this, due to the membrane-bound nature of the histidine kinase PmrB, in vitro studies on PmrAB have been predominantly limited to the response regulator PmrA. In this work, we counter these limitations by producing a recombinant truncation of the cytosolic portion of PmrB (PmrBc) that retains its ATP binding, autophosphorylation, and phosphotransfer functions. Subsequently, in vivo phosphorylation assays using this protein construct allowed for the evaluation of five compounds (IMD-0354, NDM-265, NDM-455, NDM-463, and NDM-497) that act as PmrBc inhibitors capable of preventing autophosphorylation and phosphotransfer independently. These compounds have been shown to eliminate colistin resistance in vivo. Finally, these results, paired with mass spectrometry and limited proteolysis investigations, enabled us to determine the mechanism of action of these compounds as well as their likely binding site on the ATP-lid of PmrB.
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Affiliation(s)
- Alexander D Hondros
- Department of Biochemistry & Molecular Biology, Brody School of Medicine East Carolina University, Greenville, North Carolina 27834, United States
| | - Milah M Young
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Felicia E Jaimes
- Department of Biochemistry & Molecular Biology, Brody School of Medicine East Carolina University, Greenville, North Carolina 27834, United States
| | - Jude Kinkead
- Department of Biochemistry & Molecular Biology, Brody School of Medicine East Carolina University, Greenville, North Carolina 27834, United States
| | - Richele J Thompson
- Department of Biochemistry & Molecular Biology, Brody School of Medicine East Carolina University, Greenville, North Carolina 27834, United States
| | - Christian Melander
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - John Cavanagh
- Department of Biochemistry & Molecular Biology, Brody School of Medicine East Carolina University, Greenville, North Carolina 27834, United States
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Kamoshida G, Yamada N, Yamaguchi D, Yahiro K, Morita Y. Colistin Resistance in Acinetobacter baumannii: Basic and Clinical Insights. Biol Pharm Bull 2025; 48:213-221. [PMID: 40024691 DOI: 10.1248/bpb.b23-00642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
The emergence of drug-resistant bacteria has posed a significant problem in medical institutions worldwide. Colistin, which targets lipopolysaccharide (LPS), serves as a last-resort antimicrobial agent against multidrug-resistant Gram-negative bacteria. Nevertheless, Acinetobacter baumannii, a pathogen with a worldwide prevalence of antimicrobial resistance, has been reported to develop resistance to colistin frequently. In this review, we discuss how A. baumannii acquires resistance to colistin, focusing on modification as well as loss of LPS present in its outer membrane, which is the primary mechanism of A. baumannii's resistance to colistin. Basic and clinical insights regarding colistin resistance in A. baumannii have been discussed in isolation. Therefore, we discuss the relationship between these 2 colistin resistance mechanisms in terms of the frequency and fitness of genetic mutations based on the insights from basic studies and clinical settings. We concluded that understanding the detailed mechanisms of colistin drug resistance requires a comprehensive understanding of both the frequency of mutations and the effects of selection pressure. Finally, we highlight the importance of promoting research from both basic science and clinical perspectives.
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Affiliation(s)
- Go Kamoshida
- Department of Infection Control Science, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
- Laboratory of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, 5 Misasagi-nakauchi-cho, Yamashina-ku, Kyoto 607-8412, Japan
| | - Noriteru Yamada
- Laboratory of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, 5 Misasagi-nakauchi-cho, Yamashina-ku, Kyoto 607-8412, Japan
| | - Daiki Yamaguchi
- Laboratory of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, 5 Misasagi-nakauchi-cho, Yamashina-ku, Kyoto 607-8412, Japan
| | - Kinnosuke Yahiro
- Laboratory of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, 5 Misasagi-nakauchi-cho, Yamashina-ku, Kyoto 607-8412, Japan
| | - Yuji Morita
- Department of Infection Control Science, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
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5
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Islam MM, Jung DE, Shin WS, Oh MH. Colistin Resistance Mechanism and Management Strategies of Colistin-Resistant Acinetobacter baumannii Infections. Pathogens 2024; 13:1049. [PMID: 39770308 PMCID: PMC11728550 DOI: 10.3390/pathogens13121049] [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: 11/04/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 01/16/2025] Open
Abstract
The emergence of antibiotic-resistant Acinetobacter baumannii (A. baumannii) is a pressing threat in clinical settings. Colistin is currently a widely used treatment for multidrug-resistant A. baumannii, serving as the last line of defense. However, reports of colistin-resistant strains of A. baumannii have emerged, underscoring the urgent need to develop alternative medications to combat these serious pathogens. To resist colistin, A. baumannii has developed several mechanisms. These include the loss of outer membrane lipopolysaccharides (LPSs) due to mutation of LPS biosynthetic genes, modification of lipid A (a constituent of LPSs) structure through the addition of phosphoethanolamine (PEtN) moieties to the lipid A component by overexpression of chromosomal pmrCAB operon genes and eptA gene, or acquisition of plasmid-encoded mcr genes through horizontal gene transfer. Other resistance mechanisms involve alterations of outer membrane permeability through porins, the expulsion of colistin by efflux pumps, and heteroresistance. In response to the rising threat of colistin-resistant A. baumannii, researchers have developed various treatment strategies, including antibiotic combination therapy, adjuvants to potentiate antibiotic activity, repurposing existing drugs, antimicrobial peptides, nanotechnology, photodynamic therapy, CRISPR/Cas, and phage therapy. While many of these strategies have shown promise in vitro and in vivo, further clinical trials are necessary to ensure their efficacy and widen their clinical applications. Ongoing research is essential for identifying the most effective therapeutic strategies to manage colistin-resistant A. baumannii. This review explores the genetic mechanisms underlying colistin resistance and assesses potential treatment options for this challenging pathogen.
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Affiliation(s)
- Md Minarul Islam
- Smart Animal Bio Institute, Dankook University, Cheonan 31116, Republic of Korea;
- Department of Microbiology, College of Science and Technology, Dankook University, Cheonan 31116, Republic of Korea;
| | - Da Eun Jung
- Department of Microbiology, College of Science and Technology, Dankook University, Cheonan 31116, Republic of Korea;
| | - Woo Shik Shin
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA
| | - Man Hwan Oh
- Smart Animal Bio Institute, Dankook University, Cheonan 31116, Republic of Korea;
- Department of Microbiology, College of Science and Technology, Dankook University, Cheonan 31116, Republic of Korea;
- Center for Bio-Medical Engineering Core Facility, Dankook University, Cheonan 31116, Republic of Korea
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Xu C, Cheng Q, Chen K, Kin So P, Jin W, Gu Y, Wong ILK, Chan EWC, Wong KY, Chan KF, Chen S. Repurposing cetylpyridinium chloride and domiphen bromide as phosphoethanolamine transferase inhibitor to combat colistin-resistant Enterobacterales. Microbiol Res 2024; 288:127879. [PMID: 39182419 DOI: 10.1016/j.micres.2024.127879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/26/2024] [Accepted: 08/14/2024] [Indexed: 08/27/2024]
Abstract
The emergence of plasmid-encoded colistin resistance mechanisms, MCR-1, a phosphoethanolamine transferase, rendered colistin ineffective as last resort antibiotic against severe infections caused by clinical Gram-negative bacterial pathogens. Through screening FDA-approved drug library, we identified two structurally similar compounds, namely cetylpyridinium chloride (CET) and domiphen bromide (DOM), which potentiated colistin activity in both colistin-resistant and susceptible Enterobacterales. These compounds were found to insert their long carbon chain to a hydrophobic pocket of bacterial phosphoethanolamine transferases including MCR-1, competitively blocking the binding of lipid A tail for substrate recognition and modification, resulting in the increase of bacterial sensitivity to colistin. In addition, these compounds were also found to dissipate bacterial membrane potential leading to the increase of bacterial sensitivity to colistin. Importantly, combinational use of DOM with colistin exhibited remarkable protection of test animals against infections by colistin-resistant bacteria in both mouse thigh infection and sepsis models. For mice infected by colistin-susceptible bacteria, the combinational use of DOM and colistin enable us to use lower dose of colistin to for efficient treatment. These properties render DOM excellent adjuvant candidates that help transform colistin into a highly potent antimicrobial agent for treatment of colistin-resistant Gram-negative bacterial infections and allowed us to use of a much lower dosage of colistin to reduce its toxicity against colistin-susceptible bacterial infection such as carbapenem-resistant Enterobacterales.
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Affiliation(s)
- Chen Xu
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Qipeng Cheng
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Kaichao Chen
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Pui Kin So
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Wenbin Jin
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Yanjuan Gu
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Iris Lai-King Wong
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Edward Wai Chi Chan
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Kwok-Yin Wong
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Kin Fai Chan
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
| | - Sheng Chen
- State Key Laboratory of Chemical Biology and Drug Discovery, Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
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7
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Li J, Stupak J, Haqqani AS, Harris G, Zhou H, Williamson S, Chen R, Xu HH, Chen W. Development of LC-FAIMS-MS and its application to lipidomics study of Acinetobacter baumannii infection. J Lipid Res 2024; 65:100668. [PMID: 39395788 PMCID: PMC11577210 DOI: 10.1016/j.jlr.2024.100668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 10/04/2024] [Accepted: 10/07/2024] [Indexed: 10/14/2024] Open
Abstract
The recent advances in mass spectrometry (MS) technologies have enabled comprehensive lipid profiling in biological samples. However, the robustness and efficiency of MS-based lipidomics is compromised by the complexity of biological samples. High-field asymmetric waveform ion mobility spectrometry (FAIMS) is a technology that can continuously transmit one type of ion, independent of the mass-to-charge ratio. Here we present the development and application of LC-FAIMS-MS/MS-based platform for untargeted lipidomics. We used 3 optimally balanced compensation voltages, i.e., 29 V, 34 V and 39 V, to analyze all subclasses of glycerophospholipids. The reproducibility of the method was evaluated using reference standards. The reproducibility of retention times ranged from 0.9% to 1.5% RSD; whereas RSD values of 5%-10% were observed for peak areas. More importantly, the coupling of a FAIMS device can significantly improve the robustness and efficiency. We exploited this NPLC-FAIMS-HRMS to analyze the serum lipid profiles in mice infected intranasally with Acinetobacter baumannii. The temporal profiles of serum lipids after A. baumannii inoculation were obtained for 4 h, 8 h, and 24 h. We found that nearly all ether PC and ether PE lipids were significantly decreased 8 h after inoculation. The resultant volcano plot illustrated the distribution of 28 increased and 28 decreased lipid species in mouse sera 24 h after inoculation. We also found that a single ether PE composition can comprise multiple isomeric structures, and the relative abundance of each isomer could be quantified using the newly developed NPLC-FAIMS-PRM method. We have demonstrated that the proposed LC-FAIMS-MS is a valuable platform for lipidomics.
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Affiliation(s)
- Jianjun Li
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada.
| | - Jacek Stupak
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada
| | - Arsalan S Haqqani
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada
| | - Greg Harris
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada
| | - Hongyan Zhou
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada
| | - Sam Williamson
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada
| | - Rui Chen
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada
| | - H Howard Xu
- Department of Biological Sciences, California State University Los Angeles, Los Angeles, CA, USA
| | - Wangxue Chen
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada
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8
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Bisaro F, Jackson-Litteken CD, McGuffey JC, Hooppaw AJ, Bodrog S, Jebeli L, Janet-Maitre M, Ortiz-Marquez JC, van Opijnen T, Scott NE, Di Venanzio G, Feldman MF. Diclofenac sensitizes multi-drug resistant Acinetobacter baumannii to colistin. PLoS Pathog 2024; 20:e1012705. [PMID: 39571043 PMCID: PMC11620633 DOI: 10.1371/journal.ppat.1012705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 12/05/2024] [Accepted: 10/29/2024] [Indexed: 11/27/2024] Open
Abstract
Acinetobacter baumannii causes life-threatening infections that are becoming difficult to treat due to increasing rates of multi-drug resistance (MDR) among clinical isolates. This has led the World Health Organization and the CDC to categorize MDR A. baumannii as a top priority for the research and development of new antibiotics. Colistin is the last-resort antibiotic to treat carbapenem-resistant A. baumannii. Not surprisingly, reintroduction of colistin has resulted in the emergence of colistin-resistant strains. Diclofenac is a non-steroidal anti-inflammatory drug used to treat pain and inflammation associated with arthritis. In this work, we show that diclofenac sensitizes colistin-resistant A. baumannii clinical strains to colistin in vitro and in a murine model of pneumonia. Diclofenac also reduced the colistin minimal inhibitory concentration (MIC) of Klebsiella pneumoniae and Pseudomonas aeruginosa isolates. Transcriptomic and proteomic analyses revealed an upregulation of oxidative stress-related genes and downregulation of type IV pili induced by the combination treatment. Notably, the concentrations of colistin and diclofenac effective in the murine model were substantially lower than those determined in vitro, implying a stronger synergistic effect in vivo compared to in vitro. A pilA mutant strain, lacking the primary component of the type IV pili, became sensitive to colistin in the absence of diclofenac. This suggest that the downregulation of type IV pili is key for the synergistic activity of these drugs in vivo and indicates that colistin and diclofenac exert an anti-virulence effect. Together, these results suggest that diclofenac can be repurposed with colistin to treat MDR A. baumannii.
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Affiliation(s)
- Fabiana Bisaro
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis; St. Louis, Missouri, United States of America
| | - Clay D. Jackson-Litteken
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis; St. Louis, Missouri, United States of America
| | - Jenna C. McGuffey
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis; St. Louis, Missouri, United States of America
| | - Anna J. Hooppaw
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis; St. Louis, Missouri, United States of America
| | - Sophie Bodrog
- Biology Department, Boston College; Chestnut Hill, Massachusetts, United States of America
| | - Leila Jebeli
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne; Melbourne, Australia
| | - Manon Janet-Maitre
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis; St. Louis, Missouri, United States of America
| | - Juan C. Ortiz-Marquez
- Biology Department, Boston College; Chestnut Hill, Massachusetts, United States of America
- Boston Children’s Hospital, Division of Infectious Diseases, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Tim van Opijnen
- Boston Children’s Hospital, Division of Infectious Diseases, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Nichollas E. Scott
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne; Melbourne, Australia
| | - Gisela Di Venanzio
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis; St. Louis, Missouri, United States of America
| | - Mario F. Feldman
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis; St. Louis, Missouri, United States of America
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Yamada N, Kamoshida G, Shiraishi T, Yamaguchi D, Matsuoka M, Yamauchi R, Kanda N, Kamioka R, Takemoto N, Morita Y, Fujimuro M, Yokota SI, Yahiro K. PmrAB, the two-component system of Acinetobacter baumannii, controls the phosphoethanolamine modification of lipooligosaccharide in response to metal ions. J Bacteriol 2024; 206:e0043523. [PMID: 38661375 PMCID: PMC11112996 DOI: 10.1128/jb.00435-23] [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: 12/18/2023] [Accepted: 04/03/2024] [Indexed: 04/26/2024] Open
Abstract
Acinetobacter baumannii is highly resistant to antimicrobial agents, and XDR strains have become widespread. A. baumannii has developed resistance to colistin, which is considered the last resort against XDR Gram-negative bacteria, mainly caused by lipooligosaccharide (LOS) phosphoethanolamine (pEtN) and/or galactosamine (GalN) modifications induced by mutations that activate the two-component system (TCS) pmrAB. Although PmrAB of A. baumannii has been recognized as a drug resistance factor, its function as TCS, including its regulatory genes and response factors, has not been fully elucidated. In this study, to clarify the function of PmrAB as TCS, we elucidated the regulatory genes (regulon) of PmrAB via transcriptome analysis using pmrAB-activated mutant strains. We discovered that PmrAB responds to low pH, Fe2+, Zn2+, and Al3+. A. baumannii selectively recognizes Fe2+ rather than Fe3+, and a novel region ExxxE, in addition to the ExxE motif sequence, is involved in the environmental response. Furthermore, PmrAB participates in the phosphoethanolamine modification of LOS on the bacterial surface in response to metal ions such as Al3+, contributing to the attenuation of Al3+ toxicity and development of resistance to colistin and polymyxin B in A. baumannii. This study demonstrates that PmrAB in A. baumannii not only regulates genes that play an important role in drug resistance but is also involved in responses to environmental stimuli such as metal ions and pH, and this stimulation induces LOS modification. This study reveals the importance of PmrAB in the environmental adaptation and antibacterial resistance emergence mechanisms of A. baumannii. IMPORTANCE Antimicrobial resistance (AMR) is a pressing global issue in human health. Acinetobacter baumannii is notably high on the World Health Organization's list of bacteria for which new antimicrobial agents are urgently needed. Colistin is one of the last-resort drugs used against extensively drug-resistant (XDR) Gram-negative bacteria. However, A. baumannii has become increasingly resistant to colistin, primarily by modifying its lipooligosaccharide (LOS) via activating mutations in the two-component system (TCS) PmrAB. This study comprehensively elucidates the detailed mechanism of drug resistance of PmrAB in A. baumannii as well as its biological functions. Understanding the molecular biology of these molecules, which serve as drug resistance factors and are involved in environmental recognition mechanisms in bacteria, is crucial for developing fundamental solutions to the AMR problem.
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Affiliation(s)
- Noriteru Yamada
- Laboratory of Microbiology and Infection Control, Kyoto Pharmaceutical University, Kyoto, Japan
- Laboratory of Cell Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Go Kamoshida
- Laboratory of Microbiology and Infection Control, Kyoto Pharmaceutical University, Kyoto, Japan
- Department of Infection Control Science, Meiji Pharmaceutical University, Tokyo, Japan
| | - Tsukasa Shiraishi
- Department of Microbiology, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Daiki Yamaguchi
- Laboratory of Microbiology and Infection Control, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Momoko Matsuoka
- Laboratory of Microbiology and Infection Control, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Reika Yamauchi
- Laboratory of Microbiology and Infection Control, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Nana Kanda
- Laboratory of Microbiology and Infection Control, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Roku Kamioka
- Laboratory of Microbiology and Infection Control, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Norihiko Takemoto
- Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuji Morita
- Department of Infection Control Science, Meiji Pharmaceutical University, Tokyo, Japan
| | - Masahiro Fujimuro
- Laboratory of Cell Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Shin-ichi Yokota
- Department of Microbiology, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Kinnosuke Yahiro
- Laboratory of Microbiology and Infection Control, Kyoto Pharmaceutical University, Kyoto, Japan
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10
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Bisaro F, Jackson-Litteken CD, McGuffey JC, Hooppaw AJ, Bodrog S, Jebeli L, Ortiz-Marquez JC, van Opijnen T, Scott NE, Di Venanzio G, Feldman MF. Diclofenac sensitizes multi-drug resistant Acinetobacter baumannii to colistin. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.17.594771. [PMID: 38798593 PMCID: PMC11118529 DOI: 10.1101/2024.05.17.594771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Acinetobacter baumannii causes life-threatening infections that are becoming difficult to treat due to increasing rates of multi-drug resistance (MDR) among clinical isolates. This has led the World Health Organization and the CDC to categorize MDR A. baumannii as a top priority for the research and development of new antibiotics. Colistin is the last-resort antibiotic to treat carbapenem-resistant A. baumannii . Not surprisingly, reintroduction of colistin has resulted in the emergence of colistin-resistant strains. Diclofenac is a nonsteroidal anti-inflammatory drug used to treat pain and inflammation associated with arthritis. In this work, we show that diclofenac sensitizes colistin-resistant A. baumannii clinical strains to colistin, in vitro and in a murine model of pneumonia. Diclofenac also reduced the colistin MIC of Klebsiella pneumoniae and Pseudomonas aeruginosa isolates. Transcriptomic and proteomic analyses revealed an upregulation of oxidative stress-related genes and downregulation of type IV pili induced by the combination treatment. Notably, the concentrations of colistin and diclofenac effective in the murine model were substantially lower than those determined in vitro , implying a stronger synergistic effect in vivo compared to in vitro . A pilA mutant strain, lacking the primary component of the type IV pili, became sensitive to colistin in the absence of diclofenac. This suggest that the downregulation of type IV pili is key for the synergistic activity of these drugs in vivo and indicates that colistin and diclofenac exert an anti-virulence effect. Together, these results suggest that the diclofenac can be repurposed with colistin to treat MDR A. baumannii .
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11
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Papazachariou A, Tziolos RN, Karakonstantis S, Ioannou P, Samonis G, Kofteridis DP. Treatment Strategies of Colistin Resistance Acinetobacter baumannii Infections. Antibiotics (Basel) 2024; 13:423. [PMID: 38786151 PMCID: PMC11117269 DOI: 10.3390/antibiotics13050423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 05/25/2024] Open
Abstract
Acinetobacter baumannii has emerged as a pressing challenge in clinical practice, mainly due to the development of resistance to multiple antibiotics, including colistin, one of the last-resort treatments. This review highlights all the possible mechanisms of colistin resistance and the genetic basis contributing to this resistance, such as modifications to lipopolysaccharide or lipid A structures, alterations in outer membrane permeability via porins and heteroresistance. In light of this escalating threat, the review also evaluates available treatment options. The development of new antibiotics (cefiderocol, sulbactam/durlobactam) although not available everywhere, and the use of various combinations and synergistic drug combinations (including two or more of the following: a polymyxin, ampicillin/sulbactam, carbapenems, fosfomycin, tigecycline/minocycline, a rifamycin, and aminoglycosides) are discussed in the context of overcoming colistin resistance of A. baumannii infections. Although most studied combinations are polymyxin-based combinations, non-polymyxin-based combinations have been emerging as promising options. However, clinical data remain limited and continued investigation is essential to determine optimal therapeutic strategies against colistin-resistant A. baumannii.
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Affiliation(s)
- Andria Papazachariou
- Department of Internal Medicine & Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (A.P.); (R.-N.T.); (S.K.)
| | - Renatos-Nikolaos Tziolos
- Department of Internal Medicine & Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (A.P.); (R.-N.T.); (S.K.)
| | - Stamatis Karakonstantis
- Department of Internal Medicine & Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (A.P.); (R.-N.T.); (S.K.)
| | - Petros Ioannou
- Department of Internal Medicine & Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (A.P.); (R.-N.T.); (S.K.)
| | - George Samonis
- Department of Internal Medicine & Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (A.P.); (R.-N.T.); (S.K.)
- Metropolitan Hospital, Neon Faliron, 18547 Athens, Greece
| | - Diamantis P. Kofteridis
- Department of Internal Medicine & Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (A.P.); (R.-N.T.); (S.K.)
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12
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Karampatakis T, Tsergouli K, Behzadi P. Pan-Genome Plasticity and Virulence Factors: A Natural Treasure Trove for Acinetobacter baumannii. Antibiotics (Basel) 2024; 13:257. [PMID: 38534692 DOI: 10.3390/antibiotics13030257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 02/17/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Acinetobacter baumannii is a Gram-negative pathogen responsible for a variety of community- and hospital-acquired infections. It is recognized as a life-threatening pathogen among hospitalized individuals and, in particular, immunocompromised patients in many countries. A. baumannii, as a member of the ESKAPE group, encompasses high genomic plasticity and simultaneously is predisposed to receive and exchange the mobile genetic elements (MGEs) through horizontal genetic transfer (HGT). Indeed, A. baumannii is a treasure trove that contains a high number of virulence factors. In accordance with these unique pathogenic characteristics of A. baumannii, the authors aim to discuss the natural treasure trove of pan-genome and virulence factors pertaining to this bacterial monster and try to highlight the reasons why this bacterium is a great concern in the global public health system.
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Affiliation(s)
| | - Katerina Tsergouli
- Microbiology Department, Agios Pavlos General Hospital, 55134 Thessaloniki, Greece
| | - Payam Behzadi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran 37541-374, Iran
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13
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Lucidi M, Imperi F, Artuso I, Capecchi G, Spagnoli C, Visaggio D, Rampioni G, Leoni L, Visca P. Phage-mediated colistin resistance in Acinetobacter baumannii. Drug Resist Updat 2024; 73:101061. [PMID: 38301486 DOI: 10.1016/j.drup.2024.101061] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 01/24/2024] [Accepted: 01/24/2024] [Indexed: 02/03/2024]
Abstract
AIMS Antimicrobial resistance is a global threat to human health, and Acinetobacter baumannii is a paradigmatic example of how rapidly bacteria become resistant to clinically relevant antimicrobials. The emergence of multidrug-resistant A. baumannii strains has forced the revival of colistin as a last-resort drug, suddenly leading to the emergence of colistin resistance. We investigated the genetic and molecular basis of colistin resistance in A. baumannii, and the mechanisms implicated in its regulation and dissemination. METHODS Comparative genomic analysis was combined with genetic, biochemical, and phenotypic assays to characterize Φ19606, an A. baumannii temperate bacteriophage that carries a colistin resistance gene. RESULTS Ф19606 was detected in 41% of 523 A. baumannii complete genomes and demonstrated to act as a mobile vehicle of the colistin resistance gene eptA1, encoding a functional lipid A phosphoethanolamine transferase. The eptA1 gene is coregulated with its chromosomal homolog pmrC via the PmrAB two-component system and confers colistin resistance when induced by low calcium and magnesium levels. Resistance selection assays showed that the eptA1-harbouring phage Ф19606 promotes the emergence of spontaneous colistin-resistant mutants. CONCLUSIONS Φ19606 is an unprecedented example of a self-transmissible phage vector implicated in the dissemination of colistin resistance.
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Affiliation(s)
- Massimiliano Lucidi
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy; NBFC, National Biodiversity Future Center, piazza Marina 61, 90133 Palermo, Italy.
| | - Francesco Imperi
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy; NBFC, National Biodiversity Future Center, piazza Marina 61, 90133 Palermo, Italy; Santa Lucia Foundation IRCCS, Via Ardeatina 306/354, 00179 Rome, Italy
| | - Irene Artuso
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy
| | - Giulia Capecchi
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy
| | - Cinzia Spagnoli
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy
| | - Daniela Visaggio
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy; NBFC, National Biodiversity Future Center, piazza Marina 61, 90133 Palermo, Italy; Santa Lucia Foundation IRCCS, Via Ardeatina 306/354, 00179 Rome, Italy
| | - Giordano Rampioni
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy; Santa Lucia Foundation IRCCS, Via Ardeatina 306/354, 00179 Rome, Italy
| | - Livia Leoni
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy
| | - Paolo Visca
- Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy; NBFC, National Biodiversity Future Center, piazza Marina 61, 90133 Palermo, Italy; Santa Lucia Foundation IRCCS, Via Ardeatina 306/354, 00179 Rome, Italy.
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14
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Ouyang Z, He W, Jiao M, Yu Q, Guo Y, Refat M, Qin Q, Zhang J, Shi Q, Zheng F, Wen Y. Mechanistic and biophysical characterization of polymyxin resistance response regulator PmrA in Acinetobacter baumannii. Front Microbiol 2024; 15:1293990. [PMID: 38476937 PMCID: PMC10927774 DOI: 10.3389/fmicb.2024.1293990] [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: 09/14/2023] [Accepted: 02/05/2024] [Indexed: 03/14/2024] Open
Abstract
Introduction Acinetobacter baumannii PmrAB is a crucial two-component regulatory system (TCS) that plays a vital role in conferring resistance to polymyxin. PmrA, a response regulator belonging to the OmpR/PhoB family, is composed of a C-terminal DNA-binding effector domain and an N-terminal receiver domain. The receiver domain can be phosphorylated by PmrB, a transmembrane sensor histidine kinase that interacts with PmrA. Once phosphorylated, PmrA undergoes a conformational change, resulting in the formation of a symmetric dimer in the receiver domain. This conformational change facilitates the recognition of promoter DNA by the DNA-binding domain of PmrA, leading to the activation of adaptive responses. Methods X-ray crystallography was carried out to solve the structure of PmrA receiver domain. Electrophoretic mobility shift assay and Isothermal titration calorimetry were recruited to validate the interaction between the recombinant PmrA protein and target DNA. Field-emission scanning electron microscopy (FE-SEM) was employed to characterize the surface morphology of A. baumannii in both the PmrA knockout and mutation strains. Results The receiver domain of PmrA follows the canonical α5β5 response regulator assembly, which undergoes dimerization upon phosphorylation and activation. Beryllium trifluoride is utilized as an aspartate phosphorylation mimic in this process. Mutations involved in phosphorylation and dimerization significantly affected the expression of downstream pmrC and naxD genes. This impact resulted in an enhanced cell surface smoothness with fewer modifications, ultimately contributing to a decrease in colistin (polymyxin E) and polymyxin B resistance. Additionally, a conservative direct-repeat DNA PmrA binding sequence TTTAAGNNNNNTTTAAG was identified at the promoter region of the pmrC and naxD gene. These findings provide structural insights into the PmrA receiver domain and reveal the mechanism of polymyxin resistance, suggesting that PmrA could be a potential drug target to reverse polymyxin resistance in Acinetobacter baumannii.
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Affiliation(s)
- Zhenlin Ouyang
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Wenbo He
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Min Jiao
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Qinyue Yu
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yucheng Guo
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Moath Refat
- The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Qian Qin
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jiaxin Zhang
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Qindong Shi
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Fang Zheng
- The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Yurong Wen
- Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, Department of Critical Care Medicine, Center for Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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15
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Kang Y, Yu K, Huang Z, Pang B, Liu S, Peng T, Li Y, Wang D. Prevalence and molecular characteristics of Shewanella infection in diarrhea patients in Beijing, China 2017-2019. Front Microbiol 2024; 15:1293577. [PMID: 38357347 PMCID: PMC10866003 DOI: 10.3389/fmicb.2024.1293577] [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: 09/13/2023] [Accepted: 01/03/2024] [Indexed: 02/16/2024] Open
Abstract
Introduction Shewanella is an important opportunistic pathogen distributed in marine environments that has caused an increasing number of clinical infections. However, there are few reports on the distribution and characteristics of Shewanella in the diarrheal pathogen spectrum. In this study, we have systematically described the prevalence of Shewanella infections in diarrhea patients in Beijing, China 2017-2019, and genome characteristics and antimicrobial susceptibility of Shewanella isolates. Methods Stool samples were collected from diarrhea patients in a surveillance project from 2017 to 2019. Shewanella strains were isolated, and identified using VITEKR 2 COMPACT and MALDI-TOF MS. Average nucleotide identity (ANI) analysis, multi-locus sequence typing (MLST), phylogenetic analysis, virulence-associated genes and antimicrobial resistance genes analysis were used for genome characteristics description. The antibiotic susceptibility test was performed with microbroth dilution method. Results 1104 fecal samples were collected, and the Shewanella detection rate was 2.36% (26/1104). The main manifestations of infection caused by Shewanella spp. were diarrhea (100%, 26/26), abdominal pain (65.38%, 17/26), and vomiting (38.46%, 10/26). The 26 isolates were classified into 3 species (S. algae (n = 18), S. indica (n = 5), and S. chilikensis (n = 3)) and 22 sequence types. Core genome single nucleotide polymorphism-based evolutionary tree identified three clone groups corresponding to three infection events in the same months in 2017 and 2019. The putative virulence-associated gene pool consisted of 56 potential virulence genes, including 19 virulence gene factors. The resistance rates of the 26 isolates to 17 antibiotics from high to low were as follows: polymyxin E (76.92%), cefotaxime (57.69%), ampicillin (50%), ampicillin-sulbactam (34.62%), nalidixic acid (15.38%), ciprofloxacin (11.54%), selectrin (3.846%,1/26), and tetracycline (3.846%, 1/26). The rate of multidrug resistance was 38.46% (10/26). Discussion Monitoring for Shewanella spp. should be added to the routine surveillance of infectious diarrhea during the epidemic season.
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Affiliation(s)
- Ying Kang
- Shunyi District Center for Disease Control and Prevention, Beijing, China
- Workstation for Microbial Infectious Disease, Shunyi District Center for Disease Control and Prevention, Beijing, China
| | - Keyi Yu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China
| | - Zhenzhou Huang
- Hangzhou Center for Disease Control and Prevention, Hangzhou, Zhejiang, China
| | - Bo Pang
- Workstation for Microbial Infectious Disease, Shunyi District Center for Disease Control and Prevention, Beijing, China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China
| | - Shengtian Liu
- Shunyi District Center for Disease Control and Prevention, Beijing, China
| | - Tao Peng
- Shunyi District Center for Disease Control and Prevention, Beijing, China
| | - Ying Li
- Shunyi District Center for Disease Control and Prevention, Beijing, China
- Workstation for Microbial Infectious Disease, Shunyi District Center for Disease Control and Prevention, Beijing, China
| | - Duochun Wang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China
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Abdul-Mutakabbir JC, Opoku NS, Tan KK, Jorth P, Nizet V, Fletcher HM, Kaye KS, Rybak MJ. Determining Susceptibility and Potential Mediators of Resistance for the Novel Polymyxin Derivative, SPR206, in Acinetobacter baumannii. Antibiotics (Basel) 2024; 13:47. [PMID: 38247606 PMCID: PMC10812597 DOI: 10.3390/antibiotics13010047] [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: 12/12/2023] [Revised: 12/30/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024] Open
Abstract
With the increase in carbapenem-resistant A. baumannii (CRAB) infections, there has been a resurgence in the use of polymyxins, specifically colistin (COL). Since the reintroduction of COL-based regimens in treating CRAB infections, several COL-resistant A. baumannii isolates have been identified, with the mechanism of resistance heavily linked with the loss of the lipopolysaccharide (LPS) layer of the bacterial outer membrane through mutations in lpxACD genes or the pmrCAB operon. SPR206, a novel polymyxin derivative, has exhibited robust activity against multidrug-resistant (MDR) A. baumannii. However, there is a dearth of knowledge regarding its efficacy in comparison with other A. baumannii-active therapeutics and whether traditional polymyxin (COL) mediators of A. baumannii resistance also translate to reduced SPR206 activity. Here, we conducted susceptibility testing using broth microdilution on 30 A. baumannii isolates (17 COL-resistant and 27 CRAB), selected 14 COL-resistant isolates for genomic sequencing analysis, and performed time-kill analyses on four COL-resistant isolates. In susceptibility testing, SPR206 demonstrated a lower range of minimum inhibitory concentrations (MICs) compared with COL, with a four-fold difference observed in MIC50 values. Mutations in lpxACD and/or pmrA and pmrB genes were detected in each of the 14 COL-resistant isolates; however, SPR206 maintained MICs ≤ 2 mg/L for 9/14 (64%) of the isolates. Finally, SPR206-based combination regimens exhibited increased synergistic and bactericidal activity compared with COL-based combination regimens irrespective of the multiple resistance genes detected. The results of this study highlight the potential utility of SPR206 in the treatment of COL-resistant A. baumannii infections.
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Affiliation(s)
- Jacinda C. Abdul-Mutakabbir
- Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA;
- Division of the Black Diaspora and African American Studies, University of California San Diego, La Jolla, CA 92093, USA
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92374, USA; (N.S.O.); (H.M.F.)
| | - Nana Sakyi Opoku
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92374, USA; (N.S.O.); (H.M.F.)
| | - Karen K. Tan
- Department of Pharmacy, Loma Linda University Medical Center, Loma Linda, CA 92374, USA;
| | - Peter Jorth
- Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Victor Nizet
- Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA;
| | - Hansel M. Fletcher
- Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92374, USA; (N.S.O.); (H.M.F.)
| | - Keith S. Kaye
- Department of Medicine, Rutgers University School of Medicine, New Brunswick, NJ 08854, USA;
| | - Michael J. Rybak
- Department of Pharmacy Practice, Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA;
- Department of Medicine, Division of Infectious Diseases, Wayne State University, Detroit, MI 48201, USA
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Khurana S, Katiyar A, Puraswani M, Sharma D, Walia K, Malhotra R, Mathur P. Molecular mechanisms of colistin- and multidrug-resistance in bacteria among patients with hospital-acquired infections. Future Sci OA 2023; 9:FSO896. [PMID: 37753358 PMCID: PMC10518808 DOI: 10.2144/fsoa-2022-0055] [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: 08/12/2022] [Accepted: 08/08/2023] [Indexed: 09/28/2023] Open
Abstract
Aim The increasing burden of resistance in Gram-negative bacteria (GNB) is becoming a major issue for hospital-acquired infections. Therefore, understanding the molecular mechanisms is important. Methodology Resistance genes of phenotypically colistin-resistant GNB (n = 60) were determined using whole genome sequencing. Antimicrobial susceptibility patterns were detected by Vitek®2 & broth microdilution. Results Of these phenotypically colistin-resistant isolates, 78% were also genetically resistant to colistin. Activation of efflux pumps, and point-mutations in pmrB, and MgrB genes conferred colistin resistance among GNB. Eight different strains of K. pneumoniae were identified and ST43 was the most prominent strain with capsular type-specific (cps) gene KL30. Discussion These results, in combination with rapid diagnostic methods, will help us better advice appropriate antimicrobial regimens.
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Affiliation(s)
- Surbhi Khurana
- Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi
| | - Amit Katiyar
- Centralized Core Research Facility, Bioinformatics Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Mamta Puraswani
- Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi
| | - Divya Sharma
- Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi
| | - Kamini Walia
- Epidemiology & Communicable Diseases, Indian Council of Medical Research
| | - Rajesh Malhotra
- Department of Orthopedics, Chief, JPNA Trauma Centre, All India Institute of Medical Sciences, New Delhi
| | - Purva Mathur
- Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi
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18
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Shahzad S, Willcox MDP, Rayamajhee B. A Review of Resistance to Polymyxins and Evolving Mobile Colistin Resistance Gene ( mcr) among Pathogens of Clinical Significance. Antibiotics (Basel) 2023; 12:1597. [PMID: 37998799 PMCID: PMC10668746 DOI: 10.3390/antibiotics12111597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/26/2023] [Accepted: 11/04/2023] [Indexed: 11/25/2023] Open
Abstract
The global rise in antibiotic resistance in bacteria poses a major challenge in treating infectious diseases. Polymyxins (e.g., polymyxin B and colistin) are last-resort antibiotics against resistant Gram-negative bacteria, but the effectiveness of polymyxins is decreasing due to widespread resistance among clinical isolates. The aim of this literature review was to decipher the evolving mechanisms of resistance to polymyxins among pathogens of clinical significance. We deciphered the molecular determinants of polymyxin resistance, including distinct intrinsic molecular pathways of resistance as well as evolutionary characteristics of mobile colistin resistance. Among clinical isolates, Acinetobacter stains represent a diversified evolution of resistance, with distinct molecular mechanisms of intrinsic resistance including naxD, lpxACD, and stkR gene deletion. On the other hand, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are usually resistant via the PhoP-PhoQ and PmrA-PmrB pathways. Molecular evolutionary analysis of mcr genes was undertaken to show relative relatedness across the ten main lineages. Understanding the molecular determinants of resistance to polymyxins may help develop suitable and effective methods for detecting polymyxin resistance determinants and the development of novel antimicrobial molecules.
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Affiliation(s)
- Shakeel Shahzad
- School of Optometry and Vision Science, University of New South Wales, Sydney, NSW 2052, Australia;
| | - Mark D. P. Willcox
- School of Optometry and Vision Science, University of New South Wales, Sydney, NSW 2052, Australia;
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19
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Gadar K, de Dios R, Kadeřábková N, Prescott TAK, Mavridou DAI, McCarthy RR. Disrupting iron homeostasis can potentiate colistin activity and overcome colistin resistance mechanisms in Gram-Negative Bacteria. Commun Biol 2023; 6:937. [PMID: 37704838 PMCID: PMC10499790 DOI: 10.1038/s42003-023-05302-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 08/29/2023] [Indexed: 09/15/2023] Open
Abstract
Acinetobacter baumannii is a Gram-negative priority pathogen that can readily overcome antibiotic treatment through a range of intrinsic and acquired resistance mechanisms. Treatment of carbapenem-resistant A. baumannii largely relies on the use of colistin in cases where other treatment options have been exhausted. However, the emergence of resistance against this last-line drug has significantly increased amongst clinical strains. In this study, we identify the phytochemical kaempferol as a potentiator of colistin activity. When administered singularly, kaempferol has no effect on growth but does impact biofilm formation. Nonetheless, co-administration of kaempferol with sub-inhibitory concentrations of colistin exposes bacteria to a metabolic Achilles heel, whereby kaempferol-induced dysregulation of iron homeostasis leads to bacterial killing. We demonstrate that this effect is due to the disruption of Fenton's reaction, and therefore to a lethal build-up of toxic reactive oxygen species in the cell. Furthermore, we show that this vulnerability can be exploited to overcome both intrinsic and acquired colistin resistance in clinical strains of A. baumannii and E. coli in vitro and in the Galleria mellonella model of infection. Overall, our findings provide a proof-of-principle demonstration that targeting iron homeostasis is a promising strategy for enhancing the efficacy of colistin and overcoming colistin-resistant infections.
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Affiliation(s)
- Kavita Gadar
- Biosciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, UK
| | - Rubén de Dios
- Biosciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, UK
| | - Nikol Kadeřábková
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA
| | | | - Despoina A I Mavridou
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA
- John Ring LaMontagne Centre for Infectious Diseases, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Ronan R McCarthy
- Biosciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, UK.
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20
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Rogga V, Kosalec I. Untying the anchor for the lipopolysaccharide: lipid A structural modification systems offer diagnostic and therapeutic options to tackle polymyxin resistance. Arh Hig Rada Toksikol 2023; 74:145-166. [PMID: 37791675 PMCID: PMC10549895 DOI: 10.2478/aiht-2023-74-3717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/01/2023] [Accepted: 07/01/2023] [Indexed: 10/05/2023] Open
Abstract
Polymyxin antibiotics are the last resort for treating patients in intensive care units infected with multiple-resistant Gram-negative bacteria. Due to their polycationic structure, their mode of action is based on an ionic interaction with the negatively charged lipid A portion of the lipopolysaccharide (LPS). The most prevalent polymyxin resistance mechanisms involve covalent modifications of lipid A: addition of the cationic sugar 4-amino-L-arabinose (L-Ara4N) and/or phosphoethanolamine (pEtN). The modified structure of lipid A has a lower net negative charge, leading to the repulsion of polymyxins and bacterial resistance to membrane disruption. Genes encoding the enzymatic systems involved in these modifications can be transferred either through chromosomes or mobile genetic elements. Therefore, new approaches to resistance diagnostics have been developed. On another note, interfering with these enzymatic systems might offer new therapeutic targets for drug discovery. This literature review focuses on diagnostic approaches based on structural changes in lipid A and on the therapeutic potential of molecules interfering with these changes.
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Affiliation(s)
- Vanessa Rogga
- University of Zagreb Faculty of Pharmacy and Biochemistry, Department of Microbiology, Zagreb, Croatia
| | - Ivan Kosalec
- University of Zagreb Faculty of Pharmacy and Biochemistry, Department of Microbiology, Zagreb, Croatia
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21
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Huang YT, Mao YC, Tseng CH, Liu CW, Liu PY. Identification of combinatorial mutations associated with colistin resistance in Shewanella algae. Microbes Infect 2023; 25:105143. [PMID: 37085044 DOI: 10.1016/j.micinf.2023.105143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 04/11/2023] [Accepted: 04/16/2023] [Indexed: 04/23/2023]
Abstract
Colistin is a last-resort antibiotic used to treat infections caused by drug-resistant gram-negative bacteria. However, the genetic mechanisms underlying colistin resistance in Shewanella algae are not well understood. In this study, we sequenced and compared the genomes of 23 mcr-negative colistin-resistant and sensitive S. algae samples from various sources. We applied a computational approach to identify combinatorial mutations associated with colistin resistance. Our analysis revealed a combination of three mutations (PmrB 451, PmrE168, PmrH292) that were strongly associated with colistin resistance in S. algae. This study provides insights into the genetic mechanisms of colistin resistance in S. algae and demonstrates the utility of a computational approach for identifying epistatic interactions among mutations. Identifying the genetic mutations responsible for colistin resistance in S. algae can inform the development of new treatments or strategies to combat infections caused by this emerging pathogen.
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Affiliation(s)
- Yao-Ting Huang
- Department of Computer Science and Information Engineering, National Chung Cheng University, Daxue Road Section 1, Minxiong Township, Chiayi County 62102, Taiwan
| | - Yan-Chiao Mao
- Division of Clinical Toxicology, Department of Emergency Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Xitun District, Taichung 40705, Taiwan
| | - Chien-Hao Tseng
- Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Xitun District, Taichung 40705, Taiwan
| | - Chia-Wei Liu
- Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Xitun District, Taichung 40705, Taiwan
| | - Po-Yu Liu
- Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Xitun District, Taichung 40705, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, 145 Xingda Rd, South District, Taichung 40227, Taiwan; Ph.D. Program in Translational Medicine, National Chung Hsing University, 145 Xingda Rd, South District, Taichung 40227, Taiwan; Department of Post-Baccalaureate Medicine, National Chung Hsing University, 145 Xingda Rd, South District, Taichung 40227, Taiwan; Genomic Center for Infectious Diseases, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4. Xitun District, Taichung 40705, Taiwan.
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22
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Khoshbakht R, Panahi S, Neshani A, Ghavidel M, Ghazvini K. Novel approaches to overcome Colistin resistance in Acinetobacter baumannii: Exploring quorum quenching as a potential solution. Microb Pathog 2023; 182:106264. [PMID: 37474078 DOI: 10.1016/j.micpath.2023.106264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/22/2023]
Abstract
Acinetobacter baumannii is responsible for a variety of infections, such as nosocomial infections. In recent years, this pathogen has gained resistance to many antibiotics, and thus, carbapenems were used to treat infections with MDR A. baumannii strains in clinical settings. However, as carbapenem-resistant isolates are becoming increasingly prevalent, Colistin is now used as the last line of defense against resistant A. baumannii strains. Unfortunately, reports are increasing on the presence of Colistin-resistant phenotypes in infections caused by A. baumannii, creating an urgent need to find a substitute way to combat these resistant isolates. Quorum sensing inhibition, also known as quorum quenching, is an efficient alternative way of reversing resistance in different Gram-negative bacteria. Quorum sensing is a mechanism used by bacteria to communicate with each other by secreting signal molecules. When the population of bacteria increases and the concentration of signal molecules reaches a certain threshold, bacteria can implement mechanisms to adapt to a hostile environment, such as biofilm formation. Biofilms have many advantages for pathogens, such as antibiotic resistance. Different studies have revealed that disrupting the biofilm of A. baumannii makes it more susceptible to antibiotics. Although very few studies have been conducted on the biofilm disruption through quorum quenching in Colistin-resistant A. baumannii, these studies and similar studies bring hope in finding an alternative way of treating the Colistin-resistant isolates. In conclusion, quorum quenching has the potential to be used against Colistin-resistant A. baumannii.
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Affiliation(s)
- Reza Khoshbakht
- Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Susan Panahi
- Department of Microbiology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alireza Neshani
- Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahdis Ghavidel
- Shahid Hasheminejad Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kiarash Ghazvini
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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23
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Zafer MM, Hussein AFA, Al-Agamy MH, Radwan HH, Hamed SM. Retained colistin susceptibility in clinical Acinetobacter baumannii isolates with multiple mutations in pmrCAB and lpxACD operons. Front Cell Infect Microbiol 2023; 13:1229473. [PMID: 37600939 PMCID: PMC10436201 DOI: 10.3389/fcimb.2023.1229473] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/10/2023] [Indexed: 08/22/2023] Open
Abstract
The progressive increase in the resistance rates to first- and second-line antibiotics has forced the reuse of colistin as last-line treatment for Acinetobacter baumannii infections, but the emergence of colistin-resistant strains is not uncommon. This has been long linked to acquired chromosomal mutations in the operons pmrCAB and lpxACD. Hence, such mutations are routinely screened in colistin-resistant strains by most studies. The current study was designed to explore the possible existence of pmrCAB and lpxACD mutations in colistin-susceptible isolates. For this purpose, the whole genome sequences of eighteen multi-/extensively drug resistant A. baumannii were generated by Illumina sequencing and screened for missense mutations of the operons pmrCAB and lpxACD. Most of the isolates belonged to global clones (GCs) including GC1 (n=2), GC2 (n=7), GC7 (n=2), GC9 (n=3), and GC11 (n=1). The minimum inhibitory concentrations (MICs) of colistin were determined by the broth microdilution assay. Seventeen isolates were fully susceptible to colistin with MICs ranging from (≤0.125 to 0.5 µg/ml). Interestingly, all colistin-susceptible isolates carried missense mutations in pmrCAB and lpxACD operons with reference to A. baumannii ATCC 19606. Overall, 34 mutations were found. Most substitutions were detected in pmrC (n=20) while no mutations were found in pmrA or lpxA. Notably, the mutation pattern of the two operons was almost conserved among the isolates that belonged to the same sequence type (ST) or GC. This was also confirmed by expanding the analysis to include A. baumannii genomes deposited in public databases. Here, we demonstrated the possible existence of missense mutations in pmrCAB and lpxACD operons in colistin-susceptible isolates, shedding light on the importance of interpreting mutations with reference to colistin-susceptible isolates of the same ST/GC to avoid the misleading impact of the ST/GC-related polymorphism. In turn, this may lead to misinterpretation of mutations and, hence, overlooking the real players in colistin resistance that are yet to be identified.
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Affiliation(s)
- Mai M. Zafer
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
| | - Amira F. A. Hussein
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
- Faculty of Applied Health Science, Galala University, Cairo, Egypt
| | - Mohamed H. Al-Agamy
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Hesham H. Radwan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Samira M. Hamed
- Department of Microbiology and Immunology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th of October, Giza, Egypt
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24
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De Gaetano GV, Lentini G, Famà A, Coppolino F, Beninati C. Antimicrobial Resistance: Two-Component Regulatory Systems and Multidrug Efflux Pumps. Antibiotics (Basel) 2023; 12:965. [PMID: 37370284 DOI: 10.3390/antibiotics12060965] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
The number of multidrug-resistant bacteria is rapidly spreading worldwide. Among the various mechanisms determining resistance to antimicrobial agents, multidrug efflux pumps play a noteworthy role because they export extraneous and noxious substrates from the inside to the outside environment of the bacterial cell contributing to multidrug resistance (MDR) and, consequently, to the failure of anti-infective therapies. The expression of multidrug efflux pumps can be under the control of transcriptional regulators and two-component systems (TCS). TCS are a major mechanism by which microorganisms sense and reply to external and/or intramembrane stimuli by coordinating the expression of genes involved not only in pathogenic pathways but also in antibiotic resistance. In this review, we describe the influence of TCS on multidrug efflux pump expression and activity in some Gram-negative and Gram-positive bacteria. Taking into account the strict correlation between TCS and multidrug efflux pumps, the development of drugs targeting TCS, alone or together with already discovered efflux pump inhibitors, may represent a beneficial strategy to contribute to the fight against growing antibiotic resistance.
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Affiliation(s)
| | - Germana Lentini
- Department of Human Pathology, University of Messina, 98124 Messina, Italy
| | - Agata Famà
- Department of Human Pathology, University of Messina, 98124 Messina, Italy
| | - Francesco Coppolino
- Department of Biomedical, Dental and Imaging Sciences, University of Messina, 98124 Messina, Italy
| | - Concetta Beninati
- Department of Human Pathology, University of Messina, 98124 Messina, Italy
- Scylla Biotech Srl, 98124 Messina, Italy
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25
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Oi KK, Moehle K, Schuster M, Zerbe O. Early Molecular Insights into Thanatin Analogues Binding to A. baumannii LptA. Molecules 2023; 28:4335. [PMID: 37298811 PMCID: PMC10254193 DOI: 10.3390/molecules28114335] [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: 05/04/2023] [Revised: 05/11/2023] [Accepted: 05/12/2023] [Indexed: 06/12/2023] Open
Abstract
The cationic antimicrobial ß-hairpin, thanatin, was recently developed into drug-like analogues active against carbapenem-resistant Enterobacteriaceae (CRE). The analogues represent new antibiotics with a novel mode of action targeting LptA in the periplasm and disrupting LPS transport. The compounds lose antimicrobial efficacy when the sequence identity to E. coli LptA falls below 70%. We wanted to test the thanatin analogues against LptA of a phylogenetic distant organism and investigate the molecular determinants of inactivity. Acinetobacter baumannii (A. baumannii) is a critical Gram-negative pathogen that has gained increasing attention for its multi-drug resistance and hospital burden. A. baumannii LptA shares 28% sequence identity with E. coli LptA and displays an intrinsic resistance to thanatin and thanatin analogues (MIC values > 32 µg/mL) through a mechanism not yet described. We investigated the inactivity further and discovered that these CRE-optimized derivatives can bind to LptA of A. baumannii in vitro, despite the high MIC values. Herein, we present a high-resolution structure of A. baumannii LptAm in complex with a thanatin derivative 7 and binding affinities of selected thanatin derivatives. Together, these data offer structural insights into why thanatin derivatives are inactive against A. baumannii LptA, despite binding events in vitro.
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Affiliation(s)
| | | | | | - Oliver Zerbe
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
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26
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Ko SY, Kim N, Park SY, Kim SY, Shin M, Lee JC. Acinetobacter baumannii under Acidic Conditions Induces Colistin Resistance through PmrAB Activation and Lipid A Modification. Antibiotics (Basel) 2023; 12:antibiotics12050813. [PMID: 37237716 DOI: 10.3390/antibiotics12050813] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Colistin is a last-resort antimicrobial agent for treating carbapenem-resistant Acinetobacter baumannii infections. The activation of PmrAB by several environmental signals induces colistin resistance in Gram-negative bacteria. This study investigated the molecular mechanisms of colistin resistance in A. baumannii under acidic conditions using wild-type (WT) A. baumannii 17978, ΔpmrA and ΔpmrB mutants, and pmrA-complemented strains. The pmrA or pmrB deletion did not affect the growth of A. baumannii under acidic or aerobic conditions. A. baumannii under acidic (pH 5.5) and high-iron (1 mM) conditions showed 32- and 8-fold increases in the minimum inhibitory concentrations (MICs) of colistin, respectively. The ΔpmrA and ΔpmrB mutants at pH 5.5 showed a significant decrease in colistin MICs compared to the WT strain at pH 5.5. No difference in colistin MICs was observed between WT and mutant strains under high-iron conditions. The pmrCAB expression significantly increased in the WT strain at pH 5.5 compared to the WT strain at pH 7.0. The pmrC expression significantly decreased in two mutant strains at pH 5.5 compared to the WT strain at pH 5.5. The PmrA protein was expressed in the ΔpmrA strain carrying ppmrA_FLAG plasmids at pH 5.5 but not at pH 7.0. Lipid A modification by the addition of phosphoethanolamine was observed in the WT strain at pH 5.5. In conclusion, this study demonstrated that A. baumannii under acidic conditions induces colistin resistance via the activation of pmrCAB operon and subsequent lipid A modification.
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Affiliation(s)
- Seo-Yeon Ko
- Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Nayeong Kim
- Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Seong-Yong Park
- Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Seong-Yeop Kim
- Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Minsang Shin
- Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Je-Chul Lee
- Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
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27
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Jonkergouw C, Beyeh NK, Osmekhina E, Leskinen K, Taimoory SM, Fedorov D, Anaya-Plaza E, Kostiainen MA, Trant JF, Ras RHA, Saavalainen P, Linder MB. Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Nat Commun 2023; 14:2141. [PMID: 37059703 PMCID: PMC10104825 DOI: 10.1038/s41467-023-37749-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 03/29/2023] [Indexed: 04/16/2023] Open
Abstract
The limited diversity in targets of available antibiotic therapies has put tremendous pressure on the treatment of bacterial pathogens, where numerous resistance mechanisms that counteract their function are becoming increasingly prevalent. Here, we utilize an unconventional anti-virulence screen of host-guest interacting macrocycles, and identify a water-soluble synthetic macrocycle, Pillar[5]arene, that is non-bactericidal/bacteriostatic and has a mechanism of action that involves binding to both homoserine lactones and lipopolysaccharides, key virulence factors in Gram-negative pathogens. Pillar[5]arene is active against Top Priority carbapenem- and third/fourth-generation cephalosporin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, suppressing toxins and biofilms and increasing the penetration and efficacy of standard-of-care antibiotics in combined administrations. The binding of homoserine lactones and lipopolysaccharides also sequesters their direct effects as toxins on eukaryotic membranes, neutralizing key tools that promote bacterial colonization and impede immune defenses, both in vitro and in vivo. Pillar[5]arene evades both existing antibiotic resistance mechanisms, as well as the build-up of rapid tolerance/resistance. The versatility of macrocyclic host-guest chemistry provides ample strategies for tailored targeting of virulence in a wide range of Gram-negative infectious diseases.
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Affiliation(s)
- Christopher Jonkergouw
- Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland.
| | - Ngong Kodiah Beyeh
- Oakland University, Department of Chemistry, 146 Library Drive, Rochester, MI, 48309-4479, USA
- Aalto University, School of Science, Department of Applied Physics, Puumiehenkuja 2, Espoo, Finland
| | - Ekaterina Osmekhina
- Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland
| | - Katarzyna Leskinen
- University of Helsinki, Translational Immunology Research Program, Haartmaninkatu 8, 0014, Helsinki, Finland
| | - S Maryamdokht Taimoory
- University of Windsor, Department of Chemistry and Biochemistry, Windsor, ON, N9B 3P4, Canada
- University of Michigan, Department of Chemistry, Ann Arbor, MI, USA
| | - Dmitrii Fedorov
- Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland
| | - Eduardo Anaya-Plaza
- Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland
| | - Mauri A Kostiainen
- Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland
| | - John F Trant
- University of Windsor, Department of Chemistry and Biochemistry, Windsor, ON, N9B 3P4, Canada
| | - Robin H A Ras
- Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland
- Aalto University, School of Science, Department of Applied Physics, Puumiehenkuja 2, Espoo, Finland
| | - Päivi Saavalainen
- University of Helsinki, Translational Immunology Research Program, Haartmaninkatu 8, 0014, Helsinki, Finland.
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
| | - Markus B Linder
- Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, Kemistintie 1, 02150, Espoo, Finland.
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Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology. Antibiotics (Basel) 2023; 12:antibiotics12030516. [PMID: 36978383 PMCID: PMC10044110 DOI: 10.3390/antibiotics12030516] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/17/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Acinetobacter baumannii is recognized as a clinically significant pathogen causing a wide spectrum of nosocomial infections. Colistin was considered a last-resort antibiotic for the treatment of infections caused by multidrug-resistant A. baumannii. Since the reintroduction of colistin, a number of mechanisms of colistin resistance in A. baumannii have been reported, including complete loss of LPS by inactivation of the biosynthetic pathway, modifications of target LPS driven by the addition of phosphoethanolamine (PEtN) moieties to lipid A mediated by the chromosomal pmrCAB operon and eptA gene-encoded enzymes or plasmid-encoded mcr genes and efflux of colistin from the cell. In addition to resistance to colistin, widespread heteroresistance is another feature of A. baumannii that leads to colistin treatment failure. This review aims to present a critical assessment of relevant published (>50 experimental papers) up-to-date knowledge on the molecular mechanisms of colistin resistance in A. baumannii with a detailed review of implicated mutations and the global distribution of colistin-resistant strains.
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Goic-Barisic I, Music MS, Drcelic M, Tuncbilek S, Akca G, Jakovac S, Tonkić M, Hrenovic J. Molecular characterisation of colistin and carbapenem-resistant clinical isolates of Acinetobacter baumannii from Southeast Europe. J Glob Antimicrob Resist 2023; 33:26-30. [PMID: 36878462 DOI: 10.1016/j.jgar.2023.02.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 02/26/2023] [Accepted: 02/28/2023] [Indexed: 03/07/2023] Open
Abstract
OBJECTIVES To characterise 11 colistin- and carbapenem-resistant Acinetobacter baumannii isolates recently emerging in hospital settings. METHODS A. baumannii isolates were collected from hospitalised patients under colistin treatment in three countries of Southeast Europe: Turkey, Croatia, and Bosnia and Herzegovina. Isolates were identified using molecular methods. RESULTS Isolates from Turkey and Croatia belong to the sequence types ST195 or ST281 of the clone lineage 2, while the single isolate from Bosnia and Herzegovina belongs to the ST231 of clone lineage 1. All isolates turned out to be highly resistant to colistin (MIC ≥ 16 mg/L) and have point mutations in pmrCAB operon genes. The colistin-resistant isolate from Bosnia and Herzegovina had a unique P170L point mutation in the pmrB gene and the R125H point mutation in the pmrC gene. The L20S mutation in the pmrA gene was detected only in isolates from Croatia and has never been reported before in isolates from this country. CONCLUSION Colistin resistance in A. baumannii in hospitalised patients receiving colistin treatment is a result of chromosomal mutations. The pattern of point mutations in pmrCAB genes suggests a spread of specific colistin-resistant isolates within the hospital.
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Affiliation(s)
- Ivana Goic-Barisic
- University Hospital of Split, Department of Clinical Microbiology, Split, Croatia; University of Split School of Medicine, Split, Croatia.
| | | | - Marina Drcelic
- University of Zagreb Faculty of Science, Department of Biology, Zagreb, Croatia
| | - Semra Tuncbilek
- Ufuk University Medical School, Department of Infectious Diseases and Clinical Microbiology, Ankara, Turkey
| | - Gulcin Akca
- Gazi University Faculty of Dentistry, Department of Medical Microbiology, Ankara, Turkey
| | - Sanja Jakovac
- University Clinical Hospital Mostar, Department of Microbiology and Molecular Diagnostics, Mostar, Bosnia and Herzegovina; University of Mostar School of Medicine, Mostar, Bosnia and Herzegovina
| | - Marija Tonkić
- University Hospital of Split, Department of Clinical Microbiology, Split, Croatia; University of Split School of Medicine, Split, Croatia
| | - Jasna Hrenovic
- University of Zagreb Faculty of Science, Department of Biology, Zagreb, Croatia
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Shadan A, Pathak A, Ma Y, Pathania R, Singh RP. Deciphering the virulence factors, regulation, and immune response to Acinetobacter baumannii infection. Front Cell Infect Microbiol 2023; 13:1053968. [PMID: 36968113 PMCID: PMC10038080 DOI: 10.3389/fcimb.2023.1053968] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Deciphering the virulence factors, regulation, and immune response to Acinetobacter baumannii infectionAcinetobacter baumannii is a gram-negative multidrug-resistant nosocomial pathogen and a major cause of hospital acquired infetions. Carbapenem resistant A. baumannii has been categorised as a Priority1 critial pathogen by the World Health Organisation. A. baumannii is responsible for infections in hospital settings, clinical sectors, ventilator-associated pneumonia, and bloodstream infections with a mortality rates up to 35%. With the development of advanced genome sequencing, molecular mechanisms of manipulating bacterial genomes, and animal infection studies, it has become more convenient to identify the factors that play a major role in A. baumannii infection and its persistence. In the present review, we have explored the mechanism of infection, virulence factors, and various other factors associated with the pathogenesis of this organism. Additionally, the role of the innate and adaptive immune response, and the current progress in the development of innovative strategies to combat this multidrug-resistant pathogen is also discussed.
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Affiliation(s)
- Afreen Shadan
- Department of Microbiology, Dr. Shyama Prasad Mukherjee University, Ranchi, Jharkhand, India
| | - Avik Pathak
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, India
| | - Ying Ma
- College of Resources and Environment, Southwest University, Chongqing, China
- *Correspondence: Ying Ma, ; Ranjana Pathania, ; Rajnish Prakash Singh,
| | - Ranjana Pathania
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, India
- *Correspondence: Ying Ma, ; Ranjana Pathania, ; Rajnish Prakash Singh,
| | - Rajnish Prakash Singh
- Department of Bioengineering and Biotechnology, Birla Institute of Technology, Ranchi, Jharkhand, India
- *Correspondence: Ying Ma, ; Ranjana Pathania, ; Rajnish Prakash Singh,
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Swain A, Pan A. Protein Therapeutic Target Candidates Against Acinetobacter baumannii, a Pathogen of Concern to Planetary Health: A Network-Based Integrative Omics Drug Discovery Approach. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:62-74. [PMID: 36735546 DOI: 10.1089/omi.2022.0180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Acinetobacter baumannii, an opportunistic gram-negative pathogen responsible for several nosocomial infections, has developed resistance to various antibiotics. Proteins involved in the two-component system (TCS), virulence, and antibiotic resistance (AR), help this pathogen in regulating antibiotic susceptibility and virulence mechanisms. The present study reports a network-based integrative omics approach to drug discovery to identify key regulatory proteins as therapeutic candidates against A. baumannii. We collected data on the TCS, virulence, and AR proteins from various databases (P2CS, VFDB, ARDB, and PAIDB), which were subjected to network, host-pathogen, and gene expression data analysis. Network analysis identified 43 hubs, and 10 proteins were found to be interacting with human proteins associated with vital pathways. Of the 53 (43 + 10) pathogen proteins, 46 had no orthologs in the human host. Twelve proteins, namely, RpfC, Wzc, OmpR, EnvZ, BfmS, PilG, histidine kinase, ABC 3 transport family protein, outer membrane porin OprD family, CsuD, Pgm, and LpxA, were differentially expressed in the resistant strain. We propose these proteins as key regulators that warrant evaluation as therapeutic target candidates in the future. Furthermore, structure prediction of ABC 3 transport family protein was performed as a case study. The findings from this study are poised to facilitate and inform drug discovery and development against A. baumannii.
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Affiliation(s)
- Aishwarya Swain
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Archana Pan
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India
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In Vitro Pharmacokinetics of LL-37 and Oncorhyncin II Combination Against Acinetobacter baumannii. Jundishapur J Microbiol 2023. [DOI: 10.5812/jjm-131299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background: Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most common nosocomial pathogens. Antimicrobial peptides (AMPs) have been introduced as a viable alternative to antibiotics in the treatment of MDR pathogens. Objectives: This study was designed to assess the in vitro pharmacokinetics of the combination of two potent AMPs, LL-37 and oncorhyncin II, against A. baumannii (ATCC19606). Methods: The synthesized genes of oncorhyncin II and LL-37 were introduced into Escherichia coli BL21 as the expression host. The minimum inhibitory concentration (MIC), time-kills, and growth kinetics of these peptides were used to evaluate their antimicrobial efficiencies against A. baumannii (ATCC19606). Results: LL-37 and oncorhyncin II recombinant peptides showed MIC of 30.6 and 95.87 µg/mL against A. baumannii, respectively. Additive action was confirmed by combining the generated AMPs at the checkerboard approach. The combination of LL-37 and oncorhyncin II at 2 × MIC resulted in a rapid drop in log10 CFU/mL of A. baumannii in the time-kill and growth kinetic findings studies. Conclusions: The combination of the produced LL-37 and oncorhyncin II synergizes the bioactivity of the individual peptides. Therefore, these peptides or their combinations might function as novel antibiotics and be used to develop and produce new antimicrobial drugs for the treatment of infections caused by A. baumannii.
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Guan XL, Loh JYX, Lizwan M, Chan SCM, Kwan JMC, Lim TP, Koh TH, Hsu LY, Lee BTK. LipidA-IDER to Explore the Global Lipid A Repertoire of Drug-Resistant Gram-Negative Bacteria. Anal Chem 2023; 95:602-611. [PMID: 36599414 PMCID: PMC9850412 DOI: 10.1021/acs.analchem.1c03566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
With the global emergence of drug-resistant bacteria causing difficult-to-treat infections, there is an urgent need for a tool to facilitate studies on key virulence and antimicrobial resistant factors. Mass spectrometry (MS) has contributed substantially to the elucidation of the structure-function relationships of lipid A, the endotoxic component of lipopolysaccharide which also serves as an important protective barrier against antimicrobials. Here, we present LipidA-IDER, an automated structure annotation tool for system-level scale identification of lipid A from high-resolution tandem mass spectrometry (MS2) data. LipidA-IDER was validated against previously reported structures of lipid A in the reference bacteria, Escherichia coli and Pseudomonas aeruginosa. Using MS2 data of variable quality, we demonstrated LipidA-IDER annotated lipid A with a performance of 71.2% specificity and 70.9% sensitivity, offering greater accuracy than existing lipidomics software. The organism-independent workflow was further applied to a panel of six bacterial species: E. coli and Gram-negative members of ESKAPE pathogens. A comprehensive atlas comprising 188 distinct lipid A species, including remodeling intermediates, was generated and can be integrated with software including MS-DIAL and Metabokit for identification and semiquantitation. Systematic comparison of a pair of polymyxin-sensitive and polymyxin-resistant Acinetobacter baumannii isolated from a human patient unraveled multiple key lipid A structural features of polymyxin resistance within a single analysis. Probing the lipid A landscape of bacteria using LipidA-IDER thus holds immense potential for advancing our understanding of the vast diversity and structural complexity of a key lipid virulence and antimicrobial-resistant factor. LipidA-IDER is freely available at https://github.com/Systems-Biology-Of-Lipid-Metabolism-Lab/LipidA-IDER.
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Affiliation(s)
- Xue Li Guan
- Lee
Kong Chian School of Medicine, Nanyang Technological
University, Singapore 636921, Singapore,. Tel: +65 6592 3957
| | - Johnathan Yi-Xiong Loh
- Lee
Kong Chian School of Medicine, Nanyang Technological
University, Singapore 636921, Singapore
| | - Marco Lizwan
- Lee
Kong Chian School of Medicine, Nanyang Technological
University, Singapore 636921, Singapore
| | - Sharon Cui Mun Chan
- Lee
Kong Chian School of Medicine, Nanyang Technological
University, Singapore 636921, Singapore
| | - Jeric Mun Chung Kwan
- Lee
Kong Chian School of Medicine, Nanyang Technological
University, Singapore 636921, Singapore
| | - Tze Peng Lim
- Department
of Pharmacy, Singapore General Hospital, Singapore 169608, Singapore
| | - Tse Hsien Koh
- Department
of Microbiology, Singapore General Hospital, Singapore 169608, Singapore
| | - Li-Yang Hsu
- Saw Swee
Hock School of Public Health, National University
of Singapore, Singapore 117549, Singapore
| | - Bernett Teck Kwong Lee
- Lee
Kong Chian School of Medicine, Nanyang Technological
University, Singapore 636921, Singapore,Centre
for Biomedical Informatics, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore,Singapore
Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
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Seleim SM, Mostafa MS, Ouda NH, Shash RY. The role of pmrCAB genes in colistin-resistant Acinetobacter baumannii. Sci Rep 2022; 12:20951. [PMID: 36470921 PMCID: PMC9722906 DOI: 10.1038/s41598-022-25226-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 11/28/2022] [Indexed: 12/11/2022] Open
Abstract
The progressively increasing antimicrobial-resistant Acinetobacter baumannii infections have enforced the use of colistin as the last option for therapy, resulting in the colistin resistance evolution. This work aimed to study the pmrCAB expression in A. baumannii isolates as well as the presence of the mcr-1 gene. Colistin MICs of 100 A. baumannii isolates were measured using the broth microdilution assay. In four colistin-susceptible and four colistin-resistant isolates, the relative expression of the pmrA, pmrB, and pmrC genes was determined using reverse transcription PCR, and then selected isolates were sequenced using the Sanger technique. Finally, the mcr-1 gene was detected using conventional PCR. The colistin resistance rate among the studied isolates was 49%. The expression levels of pmrA and pmrB were statistically significantly higher in colistin-resistant isolates than in colistin-susceptible ones, while the pmrC expression had no statistically significant change. There was a weak positive correlation between colistin MICs and the expression levels of each of the pmrA and pmrB genes. By sequencing, two colistin-resistant strains with low pmrCAB expression showed insertion mutations 3277188_3277189T in pmrB and 1185149_1185150T in pmrC. Only one isolate (1%) was positive for the presence of mcr-1. We concluded that pmrCAB increased expression and/or mutations may cause colistin resistance in A. baumannii. However, increased pmrC expression may not necessarily result in colistin resistance. In Egypt, this is the first study to reveal the existence of mcr-1 in A. baumanni. This should attract attention in clinical settings due to the ultimate tendency of spreading colistin resistance.
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Affiliation(s)
- Shaimaa Mohamed Seleim
- grid.7776.10000 0004 0639 9286Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Marwa Salah Mostafa
- grid.7776.10000 0004 0639 9286Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nadia Hafez Ouda
- grid.7776.10000 0004 0639 9286Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rania Yahia Shash
- grid.7776.10000 0004 0639 9286Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
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Kamoshida G, Yamada N, Nakamura T, Yamaguchi D, Kai D, Yamashita M, Hayashi C, Kanda N, Sakaguchi M, Morimoto H, Sawada T, Okada T, Kaya Y, Takemoto N, Yahiro K. Preferential Selection of Low-Frequency, Lipopolysaccharide-Modified, Colistin-Resistant Mutants with a Combination of Antimicrobials in Acinetobacter baumannii. Microbiol Spectr 2022; 10:e0192822. [PMID: 36173297 PMCID: PMC9602988 DOI: 10.1128/spectrum.01928-22] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/13/2022] [Indexed: 12/31/2022] Open
Abstract
Colistin, which targets lipopolysaccharide (LPS), is used as a last-resort drug against severe infections caused by drug-resistant Acinetobacter baumannii. However, A. baumannii possesses two colistin-resistance mechanisms. LPS modification caused by mutations in pmrAB genes is often observed in clinical isolates of multidrug-resistant Gram-negative pathogens. In addition to LPS modification, A. baumannii has a unique colistin resistance mechanism, a complete loss of LPS due to mutations in the lpxACD genes, which are involved in LPS biosynthesis. This study aimed to elucidate the detailed mechanism of the emergence of colistin-resistant A. baumannii using strains with the same genetic background. Various colistin-resistant strains were generated experimentally using colistin alone and in combination with other antimicrobials, such as meropenem and ciprofloxacin, and the mutation spectrum was analyzed. In vitro selection of A. baumannii in the presence of colistin led to the emergence of strains harboring mutations in lpxACD genes, resulting in LPS-deficient colistin-resistant strains. However, combination of colistin with other antimicrobials led to the selection of pmrAB mutant strains, resulting in strains with modified LPS (LPS-modified strains). Further, the LPS-deficient strains showed decreased fitness and increased susceptibility to many antibiotics and disinfectants. As LPS-deficient strains have a higher biological cost than LPS-modified strains, our findings suggested that pmrAB mutants are more likely to be isolated in clinical settings. We provide novel insights into the mechanisms of resistance to colistin and provide substantial solutions along with precautions for facilitating current research and treatment of colistin-resistant A. baumannii infections. IMPORTANCE Acinetobacter baumannii has developed resistance to various antimicrobial drugs, and its drug-resistant strains cause nosocomial infections. Controlling these infections has become a global clinical challenge. Carbapenem antibiotics are the frontline treatment drugs for infectious diseases caused by A. baumannii. For patients with infections caused by carbapenem-resistant A. baumannii, colistin-based therapy is often the only treatment option. However, A. baumannii readily acquires resistance to colistin. Many patients infected with colistin-resistant A. baumannii undergo colistin treatment before isolation of the colistin-resistant strain, and it is hypothesized that colistin resistance predominantly emerges under selective pressure during colistin therapy. Although the concomitant use of colistin and carbapenems has been reported to have a synergistic effect in vitro against carbapenem-resistant A. baumannii strains, our observations strongly suggest the need for attention to the emergence of strains with a modified lipopolysaccharide during treatment.
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Affiliation(s)
- Go Kamoshida
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Noriteru Yamada
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Tomoka Nakamura
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Daiki Yamaguchi
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Daichi Kai
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Maho Yamashita
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Chiaki Hayashi
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Nana Kanda
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Moe Sakaguchi
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Hitoshi Morimoto
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Teppei Sawada
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Tomoko Okada
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Yuki Kaya
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Norihiko Takemoto
- Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kinnosuke Yahiro
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
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Lv M, Ye S, Hu M, Xue Y, Liang Z, Zhou X, Zhang L, Zhou J. Two-component system ArcBA modulates cell motility and biofilm formation in Dickeya oryzae. FRONTIERS IN PLANT SCIENCE 2022; 13:1033192. [PMID: 36340374 PMCID: PMC9634086 DOI: 10.3389/fpls.2022.1033192] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/11/2022] [Indexed: 06/16/2023]
Abstract
Phytopathogen Dickeya oryzae is a causal agent of rice foot rot disease and the pathogen has an array of virulence factors, such as phytotoxin zeamines, plant cell wall degrading enzymes, cell motility, and biofilms, collectively contributing to the bacterial pathogenesis. In this study, through deletion analysis of predicted regulatory genes in D. oryzae EC1, we identified a two-component system associated with the regulation of bacterial virulence. The two-component system contains a histidine kinase ArcB and a response regulator ArcA, and deletion of their coding genes resulted in changed phenotypes in cell motility, biofilm formation, and bacterial virulence. Electrophoretic mobility shift assay revealed that ArcA bound to the promoters of the bcs operon and bssS, which respectively encode enzymes for the synthesis of celluloses and a biofilm formation regulatory protein. ArcA could also bind to the promoters of three virulence associated transcriptional regulatory genes, i.e., fis, slyA and ohrR. Surprisingly, although these three regulators were shown to modulate the production of cell wall degrading enzymes and zeamines, deletion of arcB and arcA did not seem to affect these phenotypes. Taken together, the findings from this study unveiled a new two-component system associated with the bacterial pathogenesis, which contributes to the virulence of D. oryzae mainly through its action on bacterial motility and biofilm formation.
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Affiliation(s)
- Mingfa Lv
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China
- College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China
| | - Sixuan Ye
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China
| | - Ming Hu
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China
| | - Yang Xue
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China
| | - Zhibin Liang
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China
| | - Xiaofan Zhou
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, Guangdong Province, China
| | - Lianhui Zhang
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, Guangdong Province, China
| | - Jianuan Zhou
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China
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Pérez Jorge G, Rodrigues dos Santos Goes IC, Gontijo MTP. Les misérables: a Parallel Between Antimicrobial Resistance and COVID-19 in Underdeveloped and Developing Countries. Curr Infect Dis Rep 2022; 24:175-186. [PMID: 36211535 PMCID: PMC9531231 DOI: 10.1007/s11908-022-00788-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2022] [Indexed: 12/02/2022]
Abstract
Purpose of Review The COVID-19 pandemic has been responsible for more than 6.3 million deaths worldwide. During the pandemic, the indiscriminate use of antibiotics has increased, contributing to the spread of multidrug-resistant bacteria. In this review, we aim to determine the spread and impact of antibiotic treatments in patients with COVID-19, focusing on underdeveloped and developing countries. Recent Findings Meta-analysis revealed that bacterial co-infections and secondary infections are relatively rare in COVID-19 patients, corresponding to less than 20% of hospitalized patients. Even so, most of these patients have received antibiotic treatments. Summary This review discusses how the COVID-19 pandemic could increase the emergence of multidrug-resistant strains to currently available antibiotics. Initially, we discussed the spread and impact of multidrug resistance of ESKAPE pathogens associated with nosocomial infections and analyzed their risk of secondary infections in patients with COVID-19. Then we highlight three factors related to the spread of resistant bacteria during the current pandemic: overprescription of antibiotics followed by self-medication. Finally, we discussed the lack of availability of diagnostic tests to discriminate the etiologic agent of a disease. All these factors lead to inappropriate use of antibiotics and, therefore, to an increase in the prevalence of resistance, which can have devastating consequences shortly. The data compiled in this study underscore the importance of epidemiological surveillance of hospital isolates to provide new strategies for preventing and controlling infections caused by multidrug-resistant bacteria. In addition, the bibliographic research also highlights the need for an improvement in antibiotic prescribing in the health system.
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Affiliation(s)
- Genesy Pérez Jorge
- Departamento de Genética, Evolução, Microbiologia e Imunologia, Instituto de Biologia, Universidade Estadual de Campinas, Rua Monteiro Lobato 255, Campinas, SP 13083-862 Brazil
- Laboratorio de Investigaciones Biomédicas, Universidad de Sucre, Cra. 28 #5-267, Sincelejo, Sucre, Colômbia
| | - Isabella Carolina Rodrigues dos Santos Goes
- Departamento de Genética, Evolução, Microbiologia e Imunologia, Instituto de Biologia, Universidade Estadual de Campinas, Rua Monteiro Lobato 255, Campinas, SP 13083-862 Brazil
| | - Marco Tulio Pardini Gontijo
- Departamento de Genética, Evolução, Microbiologia e Imunologia, Instituto de Biologia, Universidade Estadual de Campinas, Rua Monteiro Lobato 255, Campinas, SP 13083-862 Brazil
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, 10 Duke Medicine Cir, Durham, NC 27710 USA
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Afeke I, Adu-Amankwaah J, Nyarko M, Bushi A, Ablordey AS, Duah PA, I Wowui P, Orish VN. Acinetobacter baumannii-induced infective endocarditis: new insights into pathophysiology and antibiotic resistance mechanisms. Future Microbiol 2022; 17:1335-1344. [DOI: 10.2217/fmb-2021-0279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Infective endocarditis (IE), characterized by inflammation of the endocardial surface of the heart and its valves, results from infections caused by Staphylococcus, Streptococcus and Acinetobacter species and less commonly fungi. Acinetobacter-induced IE is a relatively rare condition with significant morbidity and mortality worldwide. Notably, its mortality rate is greater than that of endocarditis induced by Haemophilus species, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae. Although it is rare, Acinetobacter-induced IE caused by A. baumannii might bring unique therapeutic challenges such as increased antibiotic resistance. Therefore, it is vital to understand perfectly the possible pathophysiologic and antibiotic resistance mechanisms adopted by A. baumannii during IE. This review discusses the probable underlying pathomechanisms involved in A. baumannii-induced IE and highlights the potential antibiotic resistance mechanisms, suggesting therapeutic targets for A. baumannii-induced IE.
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Affiliation(s)
- Innocent Afeke
- Department of Medical Laboratory Sciences, School of Allied Health Sciences, University of Health & Allied Sciences, PM 31, Ho, Volta Region, Ghana
| | - Joseph Adu-Amankwaah
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
- Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Mary Nyarko
- Department of Nursing & Midwifery, Pentecost University, Sowutuom, Ghana
| | - Aisha Bushi
- Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Anthony S Ablordey
- Department of Bacteriology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Priscilla A Duah
- Department of Pharmacy, Nanjing Technology University, Nanjing, Jiangsu, China
| | - Prosperl I Wowui
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
- Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Verner N Orish
- Department of Microbiology & Immunology, School of Medicine, University of Health & Allied Sciences, Ho, Ghana
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Overcoming addition of phosphoethanolamine to lipid A mediated colistin resistance in Acinetobacter baumannii clinical isolates with colistin–sulbactam combination therapy. Sci Rep 2022; 12:11390. [PMID: 35794134 PMCID: PMC9259700 DOI: 10.1038/s41598-022-15386-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 06/23/2022] [Indexed: 01/08/2023] Open
Abstract
Overcoming colistin-resistant Acinetobacter baumannii (CoR-AB) has become a major concern due to the lack of effective antibiotics. This study aimed to explore the prevalence of CoR-AB clinical isolates in Thailand, their mechanisms of resistance, and test the efficacy of colistin plus sulbactam against CoR-AB isolates. The colistin resistance rate among carbapenem-resistant A. baumannii was 15.14%. The mcr gene or its variants were not detected in CoR-AB isolates by PCR screening. The lipid A mass spectra of CoR-AB isolates showed the additional [M–H]− ion peak at m/z = 2034 that correlated to the phosphoethanolamine (pEtN) addition to lipid A (N = 27/30). The important amino acid substitutions were found at position S14P, A138T, A227V in PmrB that are associated with overexpression of the pEtN transferase (PmrC) and contributed the pEtN addition. The lipopolysacccharide production genes (lpxACD) were not related to lipid A mass spectra. A colistin plus sulbactam combination exhibited the synergy rate at 86.7% against CoR-AB isolates compare to sulbactam (85.89% resistance) or colistin (15.14% resistance) alone. The excellent synergistic activity of colistin plus sulbactam combination has the potential for the treatment of CoR-AB infections.
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40
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Resistance mechanisms in Gram-negative bacteria. Med Intensiva 2022; 46:392-402. [PMID: 35660283 DOI: 10.1016/j.medine.2022.05.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 02/13/2022] [Indexed: 12/24/2022]
Abstract
Enterobacterales resistant to carbapenems or producing extended-spectrum β-lactamases (ESBL) and non-fermenters resistant to carbapenems present resistance to many of the antimicrobials commonly used in clinical practice, and have been recognized by the World Health Organization as a critical priority for the development of new antimicrobials. In this review, the main mechanisms of resistance of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia to β-lactams, quinolones, aminoglycosides and polymyxins will be addressed. Updated information will be presented on the importance in resistance of antimicrobial modification mechanisms (including class C or extended-spectrum β-lactamases, carbapenemases and aminoglycoside-modifying enzymes), permeability alterations due to porin or lipopolysaccharide expression disorders, production of active efflux pumps, target alterations or protection, and expression of two-component systems.
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41
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Antibacterial effect of singlet oxygen depending on bacteria surface charge. Photodiagnosis Photodyn Ther 2022; 39:102975. [PMID: 35724937 DOI: 10.1016/j.pdpdt.2022.102975] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/13/2022] [Accepted: 06/16/2022] [Indexed: 11/21/2022]
Abstract
Here, we investigated the bactericidal effects of two types of photoinduced reactive oxygen species (ROS), superoxide anion and singlet oxygen, on bacteria with distinct surface charges. We fabricated photofunctional polymer films (PFPFs) capable of generating both types of ROS, and they were subjected to photodynamic inactivation tests for 12 various strains of Acinetobacter baumannii. The results showed that the type I ROS (superoxide anion) was significantly dependent on the surface charge of the bacteria owing to charge-charge repulsion, while the type II ROS (singlet oxygen) was independent of the surface charge of the bacteria. These results would be significant in enhancing treatment efficiency in the clinical field.
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Khuntayaporn P, Thirapanmethee K, Chomnawang MT. An Update of Mobile Colistin Resistance in Non-Fermentative Gram-Negative Bacilli. Front Cell Infect Microbiol 2022; 12:882236. [PMID: 35782127 PMCID: PMC9248837 DOI: 10.3389/fcimb.2022.882236] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 05/16/2022] [Indexed: 12/14/2022] Open
Abstract
Colistin, the last resort for multidrug and extensively drug-resistant bacterial infection treatment, was reintroduced after being avoided in clinical settings from the 1970s to the 1990s because of its high toxicity. Colistin is considered a crucial treatment option for Acinetobacter baumannii and Pseudomonas aeruginosa, which are listed as critical priority pathogens for new antibiotics by the World Health Organization. The resistance mechanisms of colistin are considered to be chromosomally encoded, and no horizontal transfer has been reported. Nevertheless, in November 2015, a transmissible resistance mechanism of colistin, called mobile colistin resistance (MCR), was discovered. Up to ten families with MCR and more than 100 variants of Gram-negative bacteria have been reported worldwide. Even though few have been reported from Acinetobacter spp. and Pseudomonas spp., it is important to closely monitor the epidemiology of mcr genes in these pathogens. Therefore, this review focuses on the most recent update on colistin resistance and the epidemiology of mcr genes among non-fermentative Gram-negative bacilli, especially Acinetobacter spp. and P. aeruginosa.
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Affiliation(s)
- Piyatip Khuntayaporn
- Department of Microbiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
- Antimicrobial Resistance Interdisciplinary Group (AmRIG), Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
- *Correspondence: Piyatip Khuntayaporn,
| | - Krit Thirapanmethee
- Department of Microbiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
- Antimicrobial Resistance Interdisciplinary Group (AmRIG), Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Mullika Traidej Chomnawang
- Department of Microbiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
- Antimicrobial Resistance Interdisciplinary Group (AmRIG), Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
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Sionov RV, Steinberg D. Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria. Microorganisms 2022; 10:1239. [PMID: 35744757 PMCID: PMC9228545 DOI: 10.3390/microorganisms10061239] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/12/2022] [Accepted: 06/14/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic and recurrent bacterial infections are frequently associated with the formation of biofilms on biotic or abiotic materials that are composed of mono- or multi-species cultures of bacteria/fungi embedded in an extracellular matrix produced by the microorganisms. Biofilm formation is, among others, regulated by quorum sensing (QS) which is an interbacterial communication system usually composed of two-component systems (TCSs) of secreted autoinducer compounds that activate signal transduction pathways through interaction with their respective receptors. Embedded in the biofilms, the bacteria are protected from environmental stress stimuli, and they often show reduced responses to antibiotics, making it difficult to eradicate the bacterial infection. Besides reduced penetration of antibiotics through the intricate structure of the biofilms, the sessile biofilm-embedded bacteria show reduced metabolic activity making them intrinsically less sensitive to antibiotics. Moreover, they frequently express elevated levels of efflux pumps that extrude antibiotics, thereby reducing their intracellular levels. Some efflux pumps are involved in the secretion of QS compounds and biofilm-related materials, besides being important for removing toxic substances from the bacteria. Some efflux pump inhibitors (EPIs) have been shown to both prevent biofilm formation and sensitize the bacteria to antibiotics, suggesting a relationship between these processes. Additionally, QS inhibitors or quenchers may affect antibiotic susceptibility. Thus, targeting elements that regulate QS and biofilm formation might be a promising approach to combat antibiotic-resistant biofilm-related bacterial infections.
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Affiliation(s)
- Ronit Vogt Sionov
- The Biofilm Research Laboratory, The Institute of Biomedical and Oral Research, The Faculty of Dental Medicine, Hadassah Medical School, The Hebrew University, Jerusalem 9112102, Israel;
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Ušjak D, Novović K, Filipić B, Kojić M, Filipović N, Stevanović MM, Milenković MT. In vitro colistin susceptibility of pandrug-resistant Acinetobacter baumannii is restored in the presence of selenium nanoparticles. J Appl Microbiol 2022; 133:1197-1206. [PMID: 35612566 DOI: 10.1111/jam.15638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 02/23/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022]
Abstract
AIMS To investigate the synergistic activity of colistin and selenium nanoparticles (SeNPs) against pandrug-resistant (PDR) Acinetobacter baumannii. METHODS AND RESULTS Chequerboard and time-kill assays were employed to explore the potential synergistic interactions between colistin and SeNPs against A. baumannii isolates (8), previously determined as colistin-resistant (MIC range 16-256 μg ml-1 ). Also, whole-genome sequencing (WGS) and gene expression analyses were used to elucidate the mechanisms of colistin resistance. Exceptionally strong synergistic activity (FICI range 0.004-0.035) of colistin and SeNPs against colistin-resistant isolates was revealed. Colistin (0.5 or 1 μg ml-1 ) used in combination with SeNPs (0.5 μg ml-1 ) was able to reduce initial inoculum during the first 4 h of incubation, in contrast to colistin (0.5, 1 or 2 μg ml-1 ) alone. CONCLUSIONS These findings propose colistin/SeNPs combination as a new option to fight PDR A. baumannii, the therapeutic possibilities of which should be proved in future in vivo studies. SIGNIFICANCE AND IMPACT OF STUDY Here we present the first evidence of synergy between colistin and selenium compounds against bacteria in general. Also, WGS and gene expression analyses provide some new insights into A. baumannii colistin resistance mechanisms.
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Affiliation(s)
- Dušan Ušjak
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Katarina Novović
- Laboratory for Molecular Microbiology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Brankica Filipić
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.,Laboratory for Molecular Microbiology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Milan Kojić
- Laboratory for Molecular Microbiology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Nenad Filipović
- Institute of Technical Sciences of the Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Magdalena M Stevanović
- Institute of Technical Sciences of the Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Marina T Milenković
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
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Glover JS, Browning BD, Ticer TD, Engevik AC, Engevik MA. Acinetobacter calcoaceticus is Well Adapted to Withstand Intestinal Stressors and Modulate the Gut Epithelium. Front Physiol 2022; 13:880024. [PMID: 35685287 PMCID: PMC9170955 DOI: 10.3389/fphys.2022.880024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 04/12/2022] [Indexed: 12/22/2022] Open
Abstract
Background: The gastrointestinal tract has been speculated to serve as a reservoir for Acinetobacter, however little is known about the ecological fitness of Acinetobacter strains in the gut. Likewise, not much is known about the ability of Acinetobacter to consume dietary, or host derived nutrients or their capacity to modulate host gene expression. Given the increasing prevalence of Acinetobacter in the clinical setting, we sought to characterize how A. calcoaceticus responds to gut-related stressors and identify potential microbe-host interactions. Materials and Methods: To accomplish these aims, we grew clinical isolates and commercially available strains of A. calcoaceticus in minimal media with different levels of pH, osmolarity, ethanol and hydrogen peroxide. Utilization of nutrients was examined using Biolog phenotypic microarrays. To examine the interactions of A. calcoaceticus with the host, inverted murine organoids where the apical membrane is exposed to bacteria, were incubated with live A. calcoaceticus, and gene expression was examined by qPCR. Results: All strains grew modestly at pH 6, 5 and 4; indicating that these strains could tolerate passage through the gastrointestinal tract. All strains had robust growth in 0.1 and 0.5 M NaCl concentrations which mirror the small intestine, but differences were observed between strains in response to 1 M NaCl. Additionally, all strains tolerated up to 5% ethanol and 0.1% hydrogen peroxide. Biolog phenotypic microarrays revealed that A. calcoaceticus strains could use a range of nutrient sources, including monosaccharides, disaccharides, polymers, glycosides, acids, and amino acids. Interestingly, the commercially available A. calcoaceticus strains and one clinical isolate stimulated the pro-inflammatory cytokines Tnf, Kc, and Mcp-1 while all strains suppressed Muc13 and Muc2. Conclusion: Collectively, these data demonstrate that A. calcoaceticus is well adapted to dealing with environmental stressors of the gastrointestinal system. This data also points to the potential for Acinetobacter to influence the gut epithelium.
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Affiliation(s)
- Janiece S. Glover
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Brittney D. Browning
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Taylor D. Ticer
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Amy C. Engevik
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Melinda A. Engevik
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
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Rescuing humanity by antimicrobial peptides against colistin-resistant bacteria. Appl Microbiol Biotechnol 2022; 106:3879-3893. [PMID: 35604438 PMCID: PMC9125544 DOI: 10.1007/s00253-022-11940-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/18/2022] [Accepted: 04/21/2022] [Indexed: 12/03/2022]
Abstract
Abstract
It has been about a century since the discovery of the first antibiotic, and during this period, several antibiotics were produced and marketed. The production of high-potency antibiotics against infections led to victories, but these victories were temporary. Overuse and misuse of antibiotics have continued to the point that humanity today is almost helpless in the fight against infection. Researchers have predicted that by the middle of the new century, there will be a dark period after the production of antibiotics that doctors will encounter antibiotic-resistant infections for which there is no cure. Accordingly, researchers are looking for new materials with antimicrobial properties that will strengthen their ammunition to fight antibiotic-resistant infections. One of the most important alternatives to antibiotics introduced in the last three decades is antimicrobial peptides (AMPs), which affect a wide range of microbes. Due to their different antimicrobial properties from antibiotics, AMPs can fight and kill MDR, XDR, and colistin-resistant bacteria through a variety of mechanisms. Therefore, in this study, we intend to use the latest studies to give a complete description of AMPs, the importance of colistin-resistant bacteria, and their resistance mechanisms, and represent impact of AMPs on colistin-resistant bacteria. Key points • AMPs as limited options to kill colistin-resistant bacteria. • Challenge of antibiotics resistance, colistin resistance, and mechanisms. • What is AMPs in the war with colistin-resistant bacteria?
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The StkSR Two-Component System Influences Colistin Resistance in Acinetobacter baumannii. Microorganisms 2022; 10:microorganisms10050985. [PMID: 35630428 PMCID: PMC9146086 DOI: 10.3390/microorganisms10050985] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/13/2022] [Accepted: 04/22/2022] [Indexed: 01/27/2023] Open
Abstract
Acinetobacter baumannii is an opportunistic human pathogen responsible for numerous severe nosocomial infections. Genome analysis on the A. baumannii clinical isolate 04117201 revealed the presence of 13 two-component signal transduction systems (TCS). Of these, we examined the putative TCS named here as StkSR. The stkR response regulator was deleted via homologous recombination and its progeny, ΔstkR, was phenotypically characterized. Antibiogram analyses of ΔstkR cells revealed a two-fold increase in resistance to the clinically relevant polymyxins, colistin and polymyxin B, compared to wildtype. PAGE-separation of silver stained purified lipooligosaccharide isolated from ΔstkR and wildtype cells ruled out the complete loss of lipooligosaccharide as the mechanism of colistin resistance identified for ΔstkR. Hydrophobicity analysis identified a phenotypical change of the bacterial cells when exposed to colistin. Transcriptional profiling revealed a significant up-regulation of the pmrCAB operon in ΔstkR compared to the parent, associating these two TCS and colistin resistance. These results reveal that there are multiple levels of regulation affecting colistin resistance; the suggested ‘cross-talk’ between the StkSR and PmrAB two-component systems highlights the complexity of these systems.
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Madu Emeka P, Ineta Badg L, Estrella E, Belgira An G, Ezzat Khal H. Investigation of Colistin and Polymyxin B on Clinical Extreme Resistant Enterobacteriaceae Isolates for Surveillance Purposes. INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.699.713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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49
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Lepe J, Martínez-Martínez L. Mecanismos de resistencia en bacterias gramnegativas. Med Intensiva 2022. [DOI: 10.1016/j.medin.2022.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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50
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The Role of Colistin in the Era of New β-Lactam/β-Lactamase Inhibitor Combinations. Antibiotics (Basel) 2022; 11:antibiotics11020277. [PMID: 35203879 PMCID: PMC8868358 DOI: 10.3390/antibiotics11020277] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/17/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023] Open
Abstract
With the current crisis related to the emergence of carbapenem-resistant Gram-negative bacteria (CR-GNB), classical treatment approaches with so-called “old-fashion antibiotics” are generally unsatisfactory. Newly approved β-lactam/β-lactamase inhibitors (BLBLIs) should be considered as the first-line treatment options for carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections. However, colistin can be prescribed for uncomplicated lower urinary tract infections caused by CR-GNB by relying on its pharmacokinetic and pharmacodynamic properties. Similarly, colistin can still be regarded as an alternative therapy for infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) until new and effective agents are approved. Using colistin in combination regimens (i.e., including at least two in vitro active agents) can be considered in CRAB infections, and CRE infections with high risk of mortality. In conclusion, new BLBLIs have largely replaced colistin for the treatment of CR-GNB infections. Nevertheless, colistin may be needed for the treatment of CRAB infections and in the setting where the new BLBLIs are currently unavailable. In addition, with the advent of rapid diagnostic methods and novel antimicrobials, the application of personalized medicine has gained significant importance in the treatment of CRE infections.
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