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Bhuiya S, Kaushik S, Logheeswaran J, Karthika P, Prathiviraj R, Selvin J, Kiran GS. Emergence of Recurrent Urinary Tract Infection: Dissecting the mechanism of Antimicrobial Resistance, Host-Pathogen Interaction, and Hormonal Imbalance. Microb Pathog 2025:107698. [PMID: 40373943 DOI: 10.1016/j.micpath.2025.107698] [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: 12/16/2024] [Revised: 04/19/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025]
Abstract
Urinary tract infection is one of the most common infections worldwide, causing numerous deaths every year. The gut-bladder axis has been recently found to be a key factor in initiating UTI pathogenesis, along with the imbalance in the gut microbiome, which is associated with advanced susceptibility to rUTI. The patients who suffer from UTIs are, more often than not, the ones who have the lowest levels of butyrate-producing gut bacteria. Antibiotics cause dysbiosis in the gut and increase the growth of uropathogenic strains. Moreover, the gut-vagina and vagina-bladder axes are involved in UTIs by transferring microbial species, modulating the immune response, and developing intracellular bacterial reservoirs in the bladder. The rising usage of antibiotics has raised antimicrobial resistance (AMR) worldwide and recently worsened the treatment of UTIs. Resistance mechanisms include enzymatic hydrolysis of antibiotics, efflux systems, biofilm formation, horizontal gene transfer, and a weakened host's immune system, allowing bacteria to escape from the treatments. Besides, in pregnant women and adolescents, the alterations in sex hormone levels increase the risk of rUTIs. Knowledge of microbiota that harbor in the gut-vagina and vagina-bladder axes might lead to the invention of nonantibiotic preventive and therapeutic techniques in the future. In conclusion, this review emphasizes the need for a study to understand the host-microbe interactions, gut health, and AMR to effectively deal with and prevent recurrent UTIs. Also, the review explores a comprehensive analysis of the epigenetic network between host UTIs and marker genes in E. coli.
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Affiliation(s)
- Shraddha Bhuiya
- Department of Food Science and Technology, Pondicherry University, Puducherry 605014, India
| | - Saumya Kaushik
- Department of Food Science and Technology, Pondicherry University, Puducherry 605014, India
| | - Jwalaa Logheeswaran
- Department of Food Science and Technology, Pondicherry University, Puducherry 605014, India
| | - P Karthika
- Department of Food Science and Technology, Pondicherry University, Puducherry 605014, India
| | | | - Joseph Selvin
- Department of Microbiology, Pondicherry University, Puducherry 605014, India
| | - George Seghal Kiran
- Department of Food Science and Technology, Pondicherry University, Puducherry 605014, India.
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Sun S. Emerging antibiotic resistance by various novel proteins/enzymes. Eur J Clin Microbiol Infect Dis 2025:10.1007/s10096-025-05126-4. [PMID: 40232578 DOI: 10.1007/s10096-025-05126-4] [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: 01/06/2025] [Accepted: 04/02/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND The emergence and dissemination of antibiotic resistance represents a significant and ever-increasing global threat to human, animal, and environmental health. The explosive proliferation of resistance has ultimately been seen in all clinically used antibiotics. Infections caused by antibiotic-resistant bacteria have been associated with an estimated 4,950,000 deaths annually, with extremely limited therapeutic options and only a few new antibiotics under development. To combat this silent pandemic, a better understanding of the molecular mechanisms of antibiotic resistance is immensely needed, which not only helps to improve the efficacy of current drugs in clinical use but also design new antimicrobial agents that are less susceptible to resistance. RESULTS The past few years have witnessed a number of new advances in revealing the molecular mechanisms of AMR. Following five sophisticated mechanisms (efflux pump, antibiotics inactivation by enzymes, alteration of membrane permeability, target modification, and target protection), the roles of various novel proteins/enzymes in the acquisition of antibiotic resistance are constantly being described. They are widely used by clinical bacterial strains, playing a key role in the emergence of resistance. CONCLUSION While most of these have so far received less attention, expanding our understanding of these emerging resistance mechanisms is of crucial importance to combat the antibiotic resistance crisis in the world. This review summarizes recent advances in our knowledge of emerging resistance mechanisms in bacteria, providing an update on the current antibiotic resistance threats and encouraging researchers to develop critical strategies for overcoming the resistance.
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Affiliation(s)
- Shengwei Sun
- School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Fibre and Polymer Technology, KTH Royal Institute of Technology, Stockholm, SE-100 44, Sweden.
- School of Engineering Sciences in Chemistry, Biotechnology and Health, Science for Life Laboratory, Tomtebodavägen 23, Solna, 171 65, Sweden.
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3
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Gomes VMS, Bulla ACS, Torres PHM, Leal da Silva M. RND/HAE-1 members in the Pseudomonadota phylum: exploring multidrug resistance. Biophys Rev 2025; 17:687-699. [PMID: 40376394 PMCID: PMC12075780 DOI: 10.1007/s12551-025-01297-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 02/24/2025] [Indexed: 05/18/2025] Open
Abstract
The hydrophobe/amphiphile efflux-1 (HAE-1) family, part of the Resistance-Nodulation-Division (RND) superfamily, plays a critical role in the development of multidrug resistance (MDR) in bacteria. Known for its broad substrate transport capacity, this family of efflux pumps can actively expel a wide range of molecules, including antibiotics, salts, and dyes, thereby reducing the intracellular concentration of toxic substances. These transporters, which form efflux systems, are primarily found in bacteria within the phylum Pseudomonadota (Proteobacteria), where they are strongly associated with increased resistance and enhanced virulence, thus contributing to bacterial survival in hostile environments. In addition, efflux systems are composed of two other protein components: Membrane Fusion Proteins (MFPs) and Outer Membrane Factors (OMFs). Notably, several bacterial species identified by the World Health Organization (WHO) as urgent priorities for new antibiotic development, such as Escherichia coli and Pseudomonas aeruginosa, have well-studied HAE-1 efflux systems, such as AcrAB-TolC and MexAB-OprM. These systems efficiently transport molecules from the periplasm to the extracellular space, facilitating bacterial persistence. In this review, we examined the current knowledge of HAE-1 efflux transporters and their roles in the physiology and survival of bacteria in the Pseudomonadota phylum.
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Affiliation(s)
- Vinnícius Machado Schelk Gomes
- Programa de Pós-Graduação Em Biologia Computacional E Sistemas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil 4365, Manguinhos, Rio de Janeiro, RJ 21040-900 Brazil
| | - Ana Carolina Silva Bulla
- Programa de Pós-Graduação Em Biologia Computacional E Sistemas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil 4365, Manguinhos, Rio de Janeiro, RJ 21040-900 Brazil
| | - Pedro Henrique Monteiro Torres
- Programa de Pós-Graduação em Ciências Biológicas – Biofísica, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal Do Rio de Janeiro, Av. Carlos Chagas Filho 373 - CCS - Bloco G1-19, Cidade Universitária, Rio de Janeiro, RJ 21941-902 Brazil
| | - Manuela Leal da Silva
- Programa de Pós-Graduação Em Biologia Computacional E Sistemas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil 4365, Manguinhos, Rio de Janeiro, RJ 21040-900 Brazil
- Programa de Pós-Graduação Multicêntrico Em Ciências Fisiológicas, Instituto de Biodiversidade E Sustentabilidade NUPEM, Universidade Federal Do Rio de Janeiro, Avenida São José Do Barreto, 764. Centro, Macaé, RJ 27965-045 Brazil
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da Cunha IV, da Silva Oliveira DD, Calefi GG, Silva NBS, Martins CHG, Rezende Júnior CDO, Tsubone TM. Photosensitizer associated with efflux pump inhibitors as a strategy for photodynamic therapy against bacterial resistance. Eur J Med Chem 2025; 284:117197. [PMID: 39731789 DOI: 10.1016/j.ejmech.2024.117197] [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: 10/04/2024] [Revised: 12/01/2024] [Accepted: 12/08/2024] [Indexed: 12/30/2024]
Abstract
Antimicrobial resistance is currently one of the biggest challenges in controlling infectious diseases and was listed among the top 10 threats to global health by the World Health Organization (WHO) in 2023. The antibiotics misuse has led to the widespread emergence of antimicrobial resistance, marking the beginning of the alarming increase in antibiotic resistance. In this context, Antimicrobial Photodynamic Therapy (aPDT) has garnered significant attention from the scientific community due to its potential to effectively eliminate multidrug-resistant pathogenic bacteria and its low propensity to induce drug resistance, which bacteria can quickly develop against traditional antibiotic treatments. However, some efflux pumps can expel diverse substrates from inside the cell, including photosensitizers used in aPDT, contributing to multidrug-resistance mechanisms. Efflux Pump Inhibitors are potential solutions to combat resistance mediated by these pumps and can play a crucial role in enhancing aPDT's effectiveness against multidrug-resistant bacteria. Therefore, combining efflux pumps inhibitors with photosensitizers can possible to eliminate the pathogen more efficiently. This review summarizes the mechanisms in which bacteria resist conventional antibiotic treatment, with a particular emphasis on efflux pump-mediated resistance, and present aPDT as a promising strategy to combat antibiotic resistance. Additionally, we highlighted several molecules of photosensitizer associated with efflux pump inhibitors as potential strategies to optimize aPDT, aiming to offer a perspective on future research directions on aPDT for overcoming the limitations of antibiotic resistance.
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Affiliation(s)
- Ieda Vieira da Cunha
- Institute of Chemistry, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil
| | | | - Gabriel Guimarães Calefi
- Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil
| | | | | | | | - Tayana Mazin Tsubone
- Institute of Chemistry, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.
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5
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Bansod AP, Saha SK, Sen AR, Theerthesh M, Khandare RM. Effect of dried cauliflower leaf meal (Brassica oleracea var botrytis) dietary supplementation on the growth performance, carcass and meat characteristics of rabbits. J Anim Physiol Anim Nutr (Berl) 2024; 108:1807-1819. [PMID: 39016050 DOI: 10.1111/jpn.14017] [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: 01/02/2024] [Revised: 04/02/2024] [Accepted: 06/01/2024] [Indexed: 07/18/2024]
Abstract
The purpose of this study is to investigate the effect of feeding cauliflower leaf meal (CLM) on growth performance, nutrient utilization, carcass characteristics, histopathology and economics of rabbit production. A total of eighteen 45-day-old Newzeland White rabbits were randomly divided into three groups and fed with control (0%), 20% and 30% CLM in concentrate mixture and feeding trial continued for 3 months. Growth performance was recorded upto the end of the trial. On completion of the growth study, a digestibility trial was conducted to assess the digestibility of nutrients. Afterwards, all the experimental rabbits were slaughtered to evaluate the carcass and meat quality, and to examine histological changes in the viscera. The cost of production was calculated on the basis of partially replacing wheat bran with CLM. Results showed that the body weight gain, feed intake, feed conversion ratio and digestibility of nutrients were similar among the groups of rabbits. Further, dressing percentage, wholesome cut yield, chemical composition of meat, sensory evaluation, water holding capacity and shear force value were also comparable among all groups. However, total phenolic content, vitamin A and E, and polyunsaturated fatty acid were significantly (p < 0.05) higher and 2-Thiobarbituric acid reactive substance was significantly (p < 0.05) lower in 30% CLM-fed group. Histopathological study showed no pathological changes in viscera of rabbits fed with CLM. Moreover, the cost of production was significantly (p < 0.05) lower in 30% CLM-fed group of rabbits. The present work shows that the 30% CLM can be incorporated in concentrate mixture in rabbit diet without affecting growth performance or meat quality and successfully used in rabbit nutrition, which will be cheaper with enhanced keeping quality of meat.
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Affiliation(s)
- A P Bansod
- Animal Nutrition Division, ICAR-IVRI, Bareilly, India
| | - S K Saha
- Animal Nutrition Division, ICAR-IVRI, Bareilly, India
| | - A R Sen
- Livestock Products Technology Division, ICAR-IVRI, Bareilly, India
| | - M Theerthesh
- Animal Nutrition Division, ICAR-IVRI, Bareilly, India
| | - R M Khandare
- Animal Biotechnology Division, ICAR-IVRI, Bareilly, India
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6
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Khatoon H, Mohd Faudzi SM. Exploring quinoxaline derivatives: An overview of a new approach to combat antimicrobial resistance. Eur J Med Chem 2024; 276:116675. [PMID: 39004020 DOI: 10.1016/j.ejmech.2024.116675] [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: 05/14/2024] [Revised: 07/07/2024] [Accepted: 07/10/2024] [Indexed: 07/16/2024]
Abstract
Antimicrobial resistance (AMR) has emerged as a long-standing global issue ever since the introduction of penicillin, the first antibiotic. Scientists are constantly working to develop innovative antibiotics that are more effective and superior. Unfortunately, the misuse of antibiotics has resulted in their declining effectiveness over the years. By 2050, it is projected that approximately 10 million lives could be lost annually due to antibiotic resistance. Gaining insight into the mechanisms behind the development and transmission of AMR in well-known bacteria including Escherichia coli, Bacillus pumilus, Enterobacter aerogenes, Salmonella typhimurium, and the gut microbiota is crucial for researchers. Environmental contamination in third world and developing countries also plays a significant role in the increase of AMR. Despite the availability of numerous recognized antibiotics to combat bacterial infections, their effectiveness is diminishing due to the growing problem of AMR. The overuse of antibiotics has led to an increase in resistance rates and negative impacts on global health. This highlights the importance of implementing strong antimicrobial stewardship and improving global monitoring, as emphasized by the World Health Organization (WHO) and other organizations. In the face of these obstacles, quinoxaline derivatives have emerged as promising candidates. They are characterized by their remarkable efficacy against a broad spectrum of harmful bacteria, including strains that are resistant to multiple drugs. These compounds are known for their strong structural stability and adaptability, making them a promising and creative solution to the AMR crisis. This review aims to assess the effectiveness of quinoxaline derivatives in treating drug-resistant infections, with the goal of making a meaningful contribution to the global fight against AMR.
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Affiliation(s)
- Hena Khatoon
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
| | - Siti Munirah Mohd Faudzi
- Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia; Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, 43400, UPM Serdang, Selangor, Malaysia
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7
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Belay WY, Getachew M, Tegegne BA, Teffera ZH, Dagne A, Zeleke TK, Abebe RB, Gedif AA, Fenta A, Yirdaw G, Tilahun A, Aschale Y. Mechanism of antibacterial resistance, strategies and next-generation antimicrobials to contain antimicrobial resistance: a review. Front Pharmacol 2024; 15:1444781. [PMID: 39221153 PMCID: PMC11362070 DOI: 10.3389/fphar.2024.1444781] [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: 06/06/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
Antibacterial drug resistance poses a significant challenge to modern healthcare systems, threatening our ability to effectively treat bacterial infections. This review aims to provide a comprehensive overview of the types and mechanisms of antibacterial drug resistance. To achieve this aim, a thorough literature search was conducted to identify key studies and reviews on antibacterial resistance mechanisms, strategies and next-generation antimicrobials to contain antimicrobial resistance. In this review, types of resistance and major mechanisms of antibacterial resistance with examples including target site modifications, decreased influx, increased efflux pumps, and enzymatic inactivation of antibacterials has been discussed. Moreover, biofilm formation, and horizontal gene transfer methods has also been included. Furthermore, measures (interventions) taken to control antimicrobial resistance and next-generation antimicrobials have been discussed in detail. Overall, this review provides valuable insights into the diverse mechanisms employed by bacteria to resist the effects of antibacterial drugs, with the aim of informing future research and guiding antimicrobial stewardship efforts.
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Affiliation(s)
- Wubetu Yihunie Belay
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Melese Getachew
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Bantayehu Addis Tegegne
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Zigale Hibstu Teffera
- Department of Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Abebe Dagne
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Tirsit Ketsela Zeleke
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Rahel Belete Abebe
- Department of clinical pharmacy, College of medicine and health sciences, University of Gondar, Gondar, Ethiopia
| | - Abebaw Abie Gedif
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Abebe Fenta
- Department of Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Getasew Yirdaw
- Department of environmental health science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Adane Tilahun
- Department of Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Yibeltal Aschale
- Department of Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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8
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Sophonsri A, Kalu M, Wong-Beringer A. Comparative In Vitro Activity of Ceftazidime-Avibactam, Imipenem-Relebactam, and Meropenem-Vaborbactam against Carbapenem-Resistant Clinical Isolates of Klebsiella pneumoniae and Pseudomonas aeruginosa. Antibiotics (Basel) 2024; 13:416. [PMID: 38786144 PMCID: PMC11117357 DOI: 10.3390/antibiotics13050416] [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: 04/09/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024] Open
Abstract
Co-infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) and Pseudomonas aeruginosa (CRPA) is associated with poor outcomes and historically relied on combination therapy with toxic agents for management. However, several novel β-lactam/β-lactamase inhibitor combination agents have been developed, offering potential monotherapy options. Here, we compare the in vitro activity of ceftazidime-avibactam (CZA), imipenem-relebactam (IRL), and meropenem-vaborbactam (MVB) against both CRKP and CRPA clinical isolates. Minimum inhibitory concentrations (MICs) for each agent were determined using broth microdilution. Carbapenemase gene detection was performed for representative isolates of varying carbapenem resistance phenotypes. IRL demonstrated excellent activity against CRKP and CRPA with susceptibility rates at 95.8% and 91.7%, respectively. While CZA and MVB showed comparable susceptibility to IRL against CRKP (93.8%), susceptibility of CRPA to CZA was modest at 79.2%, whereas most CRPA strains were resistant to MVB. Of the 35 CRKP isolates tested, 91.4% (32/35) carried a blaKPC gene. Only 1 of 37 (2.7%) CRPA isolates tested carried a blaVIM gene, which conferred phenotypic resistance to all three agents. None of the CRKP strains were cross-resistant to all three agents. Source of infection and co-infection did not significantly influence antimicrobial activity for IRL and CZA; none of the CRPA isolates from co-infected patients were susceptible to MVB. Our results suggest that novel β-lactam agents with antipseudomonal activity and stability against carbapenemases, such as IRL and CZA, offer potential monotherapy options for the treatment of co-infection involving both CRKP and CRPA, but not MVB.
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Affiliation(s)
| | | | - Annie Wong-Beringer
- Department of Clinical Pharmacy, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; (A.S.); (M.K.)
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Saxena D, Maitra R, Bormon R, Czekanska M, Meiers J, Titz A, Verma S, Chopra S. Tackling the outer membrane: facilitating compound entry into Gram-negative bacterial pathogens. NPJ ANTIMICROBIALS AND RESISTANCE 2023; 1:17. [PMID: 39843585 PMCID: PMC11721184 DOI: 10.1038/s44259-023-00016-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 10/23/2023] [Indexed: 01/17/2025]
Abstract
Emerging resistance to all available antibiotics highlights the need to develop new antibiotics with novel mechanisms of action. Most of the currently used antibiotics target Gram-positive bacteria while Gram-negative bacteria easily bypass the action of most drug molecules because of their unique outer membrane. This additional layer acts as a potent barrier restricting the entry of compounds into the cell. In this scenario, several approaches have been elucidated to increase the accumulation of compounds into Gram-negative bacteria. This review includes a brief description of the physicochemical properties that can aid compounds to enter and accumulate in Gram-negative bacteria and covers different strategies to target or bypass the outer membrane-mediated barrier in Gram-negative bacterial pathogens.
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Affiliation(s)
- Deepanshi Saxena
- Department of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, UP, India
| | - Rahul Maitra
- Department of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, UP, India
| | - Rakhi Bormon
- Department of Chemistry, IIT Kanpur, Kanpur, 208016, UP, India
| | - Marta Czekanska
- Chemical Biology of Carbohydrates (CBCH), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123, Saarbrücken, Germany
- Department of Chemistry, Saarland University, 66123, Saarbrücken, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), 38124, Standort Hannover-Braunschweig, Germany
| | - Joscha Meiers
- Chemical Biology of Carbohydrates (CBCH), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123, Saarbrücken, Germany
- Department of Chemistry, Saarland University, 66123, Saarbrücken, Germany
- Deutsches Zentrum für Infektionsforschung (DZIF), 38124, Standort Hannover-Braunschweig, Germany
| | - Alexander Titz
- Chemical Biology of Carbohydrates (CBCH), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123, Saarbrücken, Germany.
- Department of Chemistry, Saarland University, 66123, Saarbrücken, Germany.
- Deutsches Zentrum für Infektionsforschung (DZIF), 38124, Standort Hannover-Braunschweig, Germany.
| | - Sandeep Verma
- Department of Chemistry, IIT Kanpur, Kanpur, 208016, UP, India.
- Center for Nanoscience, IIT Kanpur, Kanpur, 208016, UP, India.
| | - Sidharth Chopra
- Department of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, UP, India.
- AcSIR: Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Kumar S, Lekshmi M, Stephen J, Ortiz-Alegria A, Ayitah M, Varela MF. Dynamics of efflux pumps in antimicrobial resistance, persistence, and community living of Vibrionaceae. Arch Microbiol 2023; 206:7. [PMID: 38017151 DOI: 10.1007/s00203-023-03731-5] [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: 08/31/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/30/2023]
Abstract
The marine bacteria of the Vibrionaceae family are significant from the point of view of their role in the marine geochemical cycle, as well as symbionts and opportunistic pathogens of aquatic animals and humans. The well-known pathogens of this group, Vibrio cholerae, V. parahaemolyticus, and V. vulnificus, are responsible for significant morbidity and mortality associated with a range of infections from gastroenteritis to bacteremia acquired through the consumption of raw or undercooked seafood and exposure to seawater containing these pathogens. Although generally regarded as susceptible to commonly employed antibiotics, the antimicrobial resistance of Vibrio spp. has been on the rise in the last two decades, which has raised concern about future infections by these bacteria becoming increasingly challenging to treat. Diverse mechanisms of antimicrobial resistance have been discovered in pathogenic vibrios, the most important being the membrane efflux pumps, which contribute to antimicrobial resistance and their virulence, environmental fitness, and persistence through biofilm formation and quorum sensing. In this review, we discuss the evolution of antimicrobial resistance in pathogenic vibrios and some of the well-characterized efflux pumps' contributions to the physiology of antimicrobial resistance, host and environment survival, and their pathogenicity.
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Affiliation(s)
- Sanath Kumar
- QC Laboratory, Post-Harvest Technology, ICAR-Central Institute of Fisheries Education (CIFE), Mumbai, 400061, India
| | - Manjusha Lekshmi
- QC Laboratory, Post-Harvest Technology, ICAR-Central Institute of Fisheries Education (CIFE), Mumbai, 400061, India
| | - Jerusha Stephen
- QC Laboratory, Post-Harvest Technology, ICAR-Central Institute of Fisheries Education (CIFE), Mumbai, 400061, India
| | - Anely Ortiz-Alegria
- Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA
| | - Matthew Ayitah
- Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA
| | - Manuel F Varela
- Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
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11
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Sun K, Xu P, Zhang Y, Yu P, Ju Y. Bibliometric insights into the most influential papers on antibiotic adjuvants: a comprehensive analysis. Front Pharmacol 2023; 14:1276018. [PMID: 38027012 PMCID: PMC10679448 DOI: 10.3389/fphar.2023.1276018] [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: 08/11/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
Background: The utilization of antibiotic adjuvants presents a promising strategy for addressing bacterial resistance. Recently, the development of antibiotic adjuvants has attracted considerable attention from researchers in academia and industry. This study aimed to identify the most influential publications on antibiotic adjuvants and elucidate the hotspots and research trends in this field. Method: Original articles and reviews related to antibiotic adjuvants were retrieved from the Web of Science Core Collection database. The top 100 highly cited publications were selected and the visual analyses of publication outputs, countries, institutions, authors, journals, and keywords were conducted using Excel, VOSviewer, or CtieSpace software tools. Results: The top 100 cited publications concerning antibiotic adjuvants spanned the years 1977-2020, with citation counts ranging from 174 to 2,735. These publications encompassed 49 original articles and 51 reviews. The journal "Antimicrobial Agents and Chemotherapy" accounted for the highest number of publications (12%). The top 100 cited publications emanated from 39 countries, with the United States leading in production. Institutions in Canada and the United States exhibited the most substantial contributions to these highly cited publications. A total of 526 authors participated in these studies, with Robert E.W. Hancock, Laura J. V. Piddock, Xian-Zhi Li, Hiroshi Nikaido, and Olga Lomovskaya emerging as the most frequently nominated authors. The most common keywords included "E. coli", "P. aeruginosa", "S. aureus", "in-vitro activity", "antimicrobial peptide", "efflux pump inhibitor" "efflux pump", "MexAB-OprM" and "mechanism". These keywords underscored the hotspots of bacterial resistance mechanisms and the development of novel antibiotic adjuvants. Conclusion: Through the bibliometric analysis, this study identified the top 100 highly cited publications on antibiotic adjuvants. Moreover, the findings offered a comprehensive understanding of the characteristics and frontiers in this field.
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Affiliation(s)
- Ke Sun
- State Key Laboratory of Biotherapy and Cancer Center, Med-X Center for Manufacturing, Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Ping Xu
- Sichuan University Library, Sichuan University, Chengdu, China
| | - Yu Zhang
- Sichuan University Library, Sichuan University, Chengdu, China
| | - Pingjing Yu
- Sichuan University Library, Sichuan University, Chengdu, China
| | - Yuan Ju
- Sichuan University Library, Sichuan University, Chengdu, China
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12
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Akshay SD, Deekshit VK, Mohan Raj J, Maiti B. Outer Membrane Proteins and Efflux Pumps Mediated Multi-Drug Resistance in Salmonella: Rising Threat to Antimicrobial Therapy. ACS Infect Dis 2023; 9:2072-2092. [PMID: 37910638 DOI: 10.1021/acsinfecdis.3c00408] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
Despite colossal achievements in antibiotic therapy in recent decades, drug-resistant pathogens have remained a leading cause of death and economic loss globally. One such WHO-critical group pathogen is Salmonella. The extensive and inappropriate treatments for Salmonella infections have led from multi-drug resistance (MDR) to extensive drug resistance (XDR). The synergy between efflux-mediated systems and outer membrane proteins (OMPs) may favor MDR in Salmonella. Differential expression of the efflux system and OMPs (influx) and positional mutations are the factors that can be correlated to the development of drug resistance. Insights into the mechanism of influx and efflux of antibiotics can aid in developing a structurally stable molecule that can be proficient at escaping from the resistance loops in Salmonella. Understanding the strategic responsibilities and developing policies to address the surge of drug resistance at the national, regional, and global levels are the needs of the hour. In this Review, we attempt to aggregate all the available research findings and delineate the resistance mechanisms by dissecting the involvement of OMPs and efflux systems. Integrating major OMPs and the efflux system's differential expression and positional mutation in Salmonella may provide insight into developing strategic therapies for one health application.
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Affiliation(s)
- Sadanand Dangari Akshay
- Nitte (Deemed to be University), Nitte University Centre for Science Education and Research, Department of Bio & Nano Technology, Paneer Campus, Deralakatte, Mangalore-575018, India
| | - Vijaya Kumar Deekshit
- Nitte (Deemed to be University), Nitte University Centre for Science Education and Research, Department of Infectious Diseases & Microbial Genomics, Paneer Campus, Deralakatte, Mangalore-575018, India
| | - Juliet Mohan Raj
- Nitte (Deemed to be University), Nitte University Centre for Science Education and Research, Department of Infectious Diseases & Microbial Genomics, Paneer Campus, Deralakatte, Mangalore-575018, India
| | - Biswajit Maiti
- Nitte (Deemed to be University), Nitte University Centre for Science Education and Research, Department of Bio & Nano Technology, Paneer Campus, Deralakatte, Mangalore-575018, India
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13
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Avakh A, Grant GD, Cheesman MJ, Kalkundri T, Hall S. The Art of War with Pseudomonas aeruginosa: Targeting Mex Efflux Pumps Directly to Strategically Enhance Antipseudomonal Drug Efficacy. Antibiotics (Basel) 2023; 12:1304. [PMID: 37627724 PMCID: PMC10451789 DOI: 10.3390/antibiotics12081304] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/26/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Pseudomonas aeruginosa (P. aeruginosa) poses a grave clinical challenge due to its multidrug resistance (MDR) phenotype, leading to severe and life-threatening infections. This bacterium exhibits both intrinsic resistance to various antipseudomonal agents and acquired resistance against nearly all available antibiotics, contributing to its MDR phenotype. Multiple mechanisms, including enzyme production, loss of outer membrane proteins, target mutations, and multidrug efflux systems, contribute to its antimicrobial resistance. The clinical importance of addressing MDR in P. aeruginosa is paramount, and one pivotal determinant is the resistance-nodulation-division (RND) family of drug/proton antiporters, notably the Mex efflux pumps. These pumps function as crucial defenders, reinforcing the emergence of extensively drug-resistant (XDR) and pandrug-resistant (PDR) strains, which underscores the urgency of the situation. Overcoming this challenge necessitates the exploration and development of potent efflux pump inhibitors (EPIs) to restore the efficacy of existing antipseudomonal drugs. By effectively countering or bypassing efflux activities, EPIs hold tremendous potential for restoring the antibacterial activity against P. aeruginosa and other Gram-negative pathogens. This review focuses on concurrent MDR, highlighting the clinical significance of efflux pumps, particularly the Mex efflux pumps, in driving MDR. It explores promising EPIs and delves into the structural characteristics of the MexB subunit and its substrate binding sites.
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Affiliation(s)
| | | | | | | | - Susan Hall
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, QLD 4222, Australia; (A.A.); (G.D.G.); (M.J.C.); (T.K.)
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14
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Varela MF, Stephen J, Bharti D, Lekshmi M, Kumar S. Inhibition of Multidrug Efflux Pumps Belonging to the Major Facilitator Superfamily in Bacterial Pathogens. Biomedicines 2023; 11:1448. [PMID: 37239119 PMCID: PMC10216197 DOI: 10.3390/biomedicines11051448] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/07/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Bacterial pathogens resistant to multiple structurally distinct antimicrobial agents are causative agents of infectious disease, and they thus constitute a serious concern for public health. Of the various bacterial mechanisms for antimicrobial resistance, active efflux is a well-known system that extrudes clinically relevant antimicrobial agents, rendering specific pathogens recalcitrant to the growth-inhibitory effects of multiple drugs. In particular, multidrug efflux pump members of the major facilitator superfamily constitute central resistance systems in bacterial pathogens. This review article addresses the recent efforts to modulate these antimicrobial efflux transporters from a molecular perspective. Such investigations can potentially restore the clinical efficacy of infectious disease chemotherapy.
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Affiliation(s)
- Manuel F. Varela
- Department of Biology, Eastern New Mexico University, Station 33, Portales, NM 88130, USA
| | - Jerusha Stephen
- ICAR-Central Institute of Fisheries Education (CIFE), Mumbai 400061, India; (J.S.); (D.B.); (M.L.); (S.K.)
| | - Deeksha Bharti
- ICAR-Central Institute of Fisheries Education (CIFE), Mumbai 400061, India; (J.S.); (D.B.); (M.L.); (S.K.)
| | - Manjusha Lekshmi
- ICAR-Central Institute of Fisheries Education (CIFE), Mumbai 400061, India; (J.S.); (D.B.); (M.L.); (S.K.)
| | - Sanath Kumar
- ICAR-Central Institute of Fisheries Education (CIFE), Mumbai 400061, India; (J.S.); (D.B.); (M.L.); (S.K.)
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15
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Al-Sallami D, Alsultan A, Abbas KH, Clarke SR. Evaluation of efflux pump inhibitory activity of some plant extracts and using them as adjuvants to potentiate the inhibitory activity of some antibiotics against Staphylococcus aureus. Open Vet J 2023; 13:42-47. [PMID: 36777436 PMCID: PMC9897506 DOI: 10.5455/ovj.2023.v13.i1.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 12/11/2022] [Indexed: 02/05/2023] Open
Abstract
Background Antibiotic-resistant pathogens became a real global threat to human and animal health. This needs to concentrate the efforts to minimize and control these organisms. Efflux pumps are considered one of the important strategies used by bacteria to exclude harmful materials from the cell. Inhibition of these pumps can be an active strategy against multidrug resistance pathogens. There are two sources of efflux pump inhibitors that can be used, chemical and natural inhibitors. The chemical origin efflux pump inhibitors have many toxic side effects while the natural origin is characterized by a wide margin of safety for the host cell. Aim In this study, the ability of some plant extracts like (propolis show rosemary, clove, capsaicin, and cumin) to potentiate the inhibitory activity of some antibiotics such as (ciprofloxacin, erythromycin, gentamycin, tetracycline, and ampicillin) against Staphylococcus aureus pathogen were tested. Methods Efflux pump inhibitory activity of the selected plant extracts was tested using an ethidium bromide (EtBr) accumulation assay. Results The results have shown that Propolis has a significant synergistic effect in combination with ciprofloxacin, erythromycin, and gentamycin. While it has no effect with tetracycline or ampicillin. Also, no synergic effect was noticed in a combination of the minimum inhibitory concentration for the selected plant extracts (rosemary, clove, capsaicin, and cumin) with any of the tested antibiotics. Interestingly, according to the results of the EtBr accumulation assay, Propolis has potent inhibitory activity against the S. aureus (MRS usa300) pump system. Conclusion This study suggests that Propolis might act as a resistance breaker that is able to restore the activity of ciprofloxacin, erythromycin, and gentamycin against S. aureus strains, in case of the efflux-mediated antimicrobial resistance mechanisms.
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Affiliation(s)
- Dhama Al-Sallami
- Department of Physiology, Pharmacology and Biochemistry, College of Veterinary Medicine, University of Al-Qadisiyah, Al-Diwaniyah, Iraq
| | - Amjed Alsultan
- Department of Internal and Preventive Medicine, College of Veterinary Medicine, University of Al-Qadisiyah, Al-Diwaniyah, Iraq,Corresponding Author: Amjed Alsultan. Department of Internal and Preventive Medicine, College of Veterinary Medicine, University of Al-Qadisiyah, Al- Diwaniyah, Iraq.
| | - Kadhim Hassan Abbas
- Department of Veterinary Public Health, College of Veterinary Medicine, University of Al-Qadisiyah, Al-Diwaniyah, Iraq
| | - Simon R. Clarke
- Department of Physiology, Pharmacology and Biochemistry, College of Veterinary Medicine, University of Al-Qadisiyah, Al-Diwaniyah, Iraq
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16
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Lorusso AB, Carrara JA, Barroso CDN, Tuon FF, Faoro H. Role of Efflux Pumps on Antimicrobial Resistance in Pseudomonas aeruginosa. Int J Mol Sci 2022; 23:15779. [PMID: 36555423 PMCID: PMC9779380 DOI: 10.3390/ijms232415779] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open
Abstract
Antimicrobial resistance is an old and silent pandemic. Resistant organisms emerge in parallel with new antibiotics, leading to a major global public health crisis over time. Antibiotic resistance may be due to different mechanisms and against different classes of drugs. These mechanisms are usually found in the same organism, giving rise to multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. One resistance mechanism that is closely associated with the emergence of MDR and XDR bacteria is the efflux of drugs since the same pump can transport different classes of drugs. In Gram-negative bacteria, efflux pumps are present in two configurations: a transmembrane protein anchored in the inner membrane and a complex formed by three proteins. The tripartite complex has a transmembrane protein present in the inner membrane, a periplasmic protein, and a porin associated with the outer membrane. In Pseudomonas aeruginosa, one of the main pathogens associated with respiratory tract infections, four main sets of efflux pumps have been associated with antibiotic resistance: MexAB-OprM, MexXY, MexCD-OprJ, and MexEF-OprN. In this review, the function, structure, and regulation of these efflux pumps in P. aeruginosa and their actions as resistance mechanisms are discussed. Finally, a brief discussion on the potential of efflux pumps in P. aeruginosa as a target for new drugs is presented.
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Affiliation(s)
- Andre Bittencourt Lorusso
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Fiocruz, Curitiba 81350-010, Brazil
- School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná, Curitiba 80215-901, Brazil
| | - João Antônio Carrara
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Fiocruz, Curitiba 81350-010, Brazil
| | | | - Felipe Francisco Tuon
- Laboratory of Emerging Infectious Diseases, Pontifícia Universidade Católica do Paraná, Curitiba 80215-901, Brazil
| | - Helisson Faoro
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Fiocruz, Curitiba 81350-010, Brazil
- CHU de Quebec Research Center, Department of Microbiology, Infectious Disease and Immunology, University Laval, Quebec, QC G1V 0A6, Canada
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17
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Geng B, Huang X, Wu Y, He Q, Yang S. Identification and Characterization of Genes Related to Ampicillin Antibiotic Resistance in Zymomonas mobilis. Antibiotics (Basel) 2022; 11:1476. [PMID: 36358131 PMCID: PMC9686808 DOI: 10.3390/antibiotics11111476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/18/2022] [Accepted: 10/24/2022] [Indexed: 10/15/2023] Open
Abstract
Antibiotics can inhibit or kill microorganisms, while microorganisms have evolved antibiotic resistance strategies to survive antibiotics. Zymomonas mobilis is an ideal industrial microbial chassis and can tolerate multiple antibiotics. However, the mechanisms of antibiotic resistance and genes associated with antibiotic resistance have not been fully analyzed and characterized. In this study, we investigated genes associated with antibiotic resistance using bioinformatic approaches and examined genes associated with ampicillin resistance using CRISPR/Cas12a-based genome-editing technology. Six ampicillin-resistant genes (ZMO0103, ZMO0893, ZMO1094, ZMO1650, ZMO1866, and ZMO1967) were identified, and five mutant strains ZM4∆0103, ZM4∆0893, ZM4∆1094, ZM4∆1650, and ZM4∆1866 were constructed. Additionally, a four-gene mutant ZM4∆ARs was constructed by knocking out ZMO0103, ZMO0893, ZMO1094, and ZMO1650 continuously. Cell growth, morphology, and transformation efficiency of mutant strains were examined. Our results show that the cell growth of ZM4∆0103 and ZM4∆ARs was significantly inhibited with 150 μg/mL ampicillin, and cells changed to a long filament shape from a short rod shape. Moreover, the transformation efficiencies of ZM4∆0103 and ZM4∆ARs were decreased. Our results indicate that ZMO0103 is the key to ampicillin resistance in Z. mobilis, and other ampicillin-resistant genes may have a synergetic effect with it. In summary, this study identified and characterized genes related to ampicillin resistance in Z. mobilis and laid a foundation for further study of other antibiotic resistance mechanisms.
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Affiliation(s)
| | | | | | - Qiaoning He
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Environmental Microbial Technology Center of Hubei Province, School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Shihui Yang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Environmental Microbial Technology Center of Hubei Province, School of Life Sciences, Hubei University, Wuhan 430062, China
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18
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Samtiya M, Matthews KR, Dhewa T, Puniya AK. Antimicrobial Resistance in the Food Chain: Trends, Mechanisms, Pathways, and Possible Regulation Strategies. Foods 2022; 11:2966. [PMID: 36230040 PMCID: PMC9614604 DOI: 10.3390/foods11192966] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/09/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
Antimicrobial resistance (AMR) remains of major interest for different types of food stakeholders since it can negatively impact human health on a global scale. Antimicrobial-resistant bacteria and/or antimicrobial resistance genes (transfer in pathogenic bacteria) may contaminate food at any stage, from the field to retail. Research demonstrates that antimicrobial-resistant bacterial infection(s) occur more frequently in low- and middle-income countries (LMICs) than in developed countries. Worldwide, foodborne pathogens are a primary cause of morbidity and mortality. The spread of pathogenic bacteria from food to consumers may occur by direct or indirect routes. Therefore, an array of approaches both at the national and international level to control the spread of foodborne pathogens and promote food safety and security are essential. Zoonotic microbes can spread through the environment, animals, humans, and the food chain. Antimicrobial drugs are used globally to treat infections in humans and animals and prophylactically in production agriculture. Research highlights that foods may become contaminated with AMR bacteria (AMRB) during the continuum from the farm to processing to retail to the consumer. To mitigate the risk of AMRB in humans, it is crucial to control antibiotic use throughout food production, both for animal and crop agriculture. The main inferences of this review are (1) routes by which AMRB enters the food chain during crop and animal production and other modes, (2) prevention and control steps for AMRB, and (3) impact on human health if AMR is not addressed globally. A thorough perspective is presented on the gaps in current systems for surveillance of antimicrobial use in food production and/ or AMR in the food chain.
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Affiliation(s)
- Mrinal Samtiya
- Department of Nutrition Biology, Central University of Haryana, Mahendergarh 123029, India
| | - Karl R. Matthews
- Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA
| | - Tejpal Dhewa
- Department of Nutrition Biology, Central University of Haryana, Mahendergarh 123029, India
| | - Anil Kumar Puniya
- Dairy Microbiology Division, ICAR-National Dairy Research Institute, Karnal 132001, India
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19
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Repac Antić D, Parčina M, Gobin I, Petković Didović M. Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond. Antibiotics (Basel) 2022; 11:1105. [PMID: 36009974 PMCID: PMC9405089 DOI: 10.3390/antibiotics11081105] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 11/16/2022] Open
Abstract
In the era of escalating antimicrobial resistance, the need for antibacterial drugs with novel or improved modes of action (MOAs) is a health concern of utmost importance. Adding or improving the chelating abilities of existing drugs or finding new, nature-inspired chelating agents seems to be one of the major ways to ensure progress. This review article provides insight into the modes of action of antibacterial agents, class by class, through the perspective of chelation. We covered a wide scope of antibacterials, from a century-old quintessential chelating agent nitroxoline, currently unearthed due to its newly discovered anticancer and antibiofilm activities, over the commonly used antibacterial classes, to new cephalosporin cefiderocol and a potential future class of tetramates. We show the impressive spectrum of roles that chelation plays in antibacterial MOAs. This, by itself, demonstrates the importance of understanding the fundamental chemistry behind such complex processes.
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Affiliation(s)
- Davorka Repac Antić
- Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
- Department of Clinical Microbiology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia
| | - Marijo Parčina
- Institute of Medical Microbiology, Immunology and Parasitology, Bonn University Hospital, 53127 Bonn, Germany
| | - Ivana Gobin
- Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Mirna Petković Didović
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
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20
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Kaur R, Kanotra M, Sood A, Abdellatif AAH, Bhatia S, Al-Harrasi A, Aleya L, Vargas-De-La-Cruz C, Behl T. Emergence of nutriments as a nascent complementary therapy against antimicrobial resistance. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:49568-49582. [PMID: 35589902 DOI: 10.1007/s11356-022-20775-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 05/08/2022] [Indexed: 06/15/2023]
Abstract
With these growing and evolving years, antimicrobial resistance has become a great subject of interest. The idea of using natural productive ways can be an effective measure against antimicrobial resistance. The growing prevalence of antimicrobial resistance indicates that advanced natural approaches are a topic of concern for fighting the resistance. Many natural products including essential oils, flavonoids, alkaloids and botanicals have been demonstrated as effective bactericidal agents. In this review, we will discuss in detail about the relevance of such natural products to tackle the problem of antimicrobial resistance, antibiotic adjuvants that aim towards non-essential bacterial targets to reduce the prevalence of resistant bacterial infections, latest bioinformatics approach towards antibacterial drug discovery along with an understanding of biogenic nanoparticles in antimicrobial activity.
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Affiliation(s)
- Rajwinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Patiala, Punjab, India
| | - Muskan Kanotra
- Chitkara College of Pharmacy, Chitkara University, Patiala, Punjab, India
| | - Ankita Sood
- Chitkara College of Pharmacy, Chitkara University, Patiala, Punjab, India
| | - Ahmed A H Abdellatif
- Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraydah, Saudi Arabia
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
- School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Besancon, France
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima, Peru
- E-Health Research Center, Universidad de Ciencias Y Humanidades, Lima, Peru
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Patiala, Punjab, India.
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21
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Youlden G, McNeil HE, Blair JMA, Jabbari S, King JR. Mathematical Modelling Highlights the Potential for Genetic Manipulation as an Adjuvant to Counter Efflux-Mediated MDR in Salmonella. Bull Math Biol 2022; 84:56. [PMID: 35380320 PMCID: PMC8983579 DOI: 10.1007/s11538-022-01011-9] [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: 07/06/2021] [Accepted: 03/02/2022] [Indexed: 11/18/2022]
Abstract
Bacteria have developed resistance to antibiotics by various mechanisms, notable amongst these is the use of permeation barriers and the expulsion of antibiotics via efflux pumps. The resistance-nodulation-division (RND) family of efflux pumps is found in Gram-negative bacteria and a major contributor to multidrug resistance (MDR). In particular, Salmonella encodes five RND efflux pump systems: AcrAB, AcrAD, AcrEF, MdsAB and MdtAB which have different substrate ranges including many antibiotics. We produce a spatial partial differential equation (PDE) model governing the diffusion and efflux of antibiotic in Salmonella, via these RND efflux pumps. Using parameter fitting techniques on experimental data, we are able to establish the behaviour of multiple wild-type and efflux mutant Salmonella strains, which enables us to produce efflux profiles for each individual efflux pump system. By combining the model with a gene regulatory network (GRN) model of efflux regulation, we simulate how the bacteria respond to their environment. Finally, performing a parameter sensitivity analysis, we look into various different targets to inhibit the efflux pumps. The model provides an in silico framework with which to test these potential adjuvants to counter MDR.
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Affiliation(s)
- George Youlden
- School of Mathematics, University of Birmingham, Birmingham, B15 2TT, UK.
- School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, B15 2TT, UK.
| | - Helen E McNeil
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, B15 2TT, UK
| | - Jessica M A Blair
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, B15 2TT, UK
| | - Sara Jabbari
- School of Mathematics, University of Birmingham, Birmingham, B15 2TT, UK
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, B15 2TT, UK
| | - John R King
- School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK
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22
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Maringolo-Ribeiro C, Grecco JA, Bellato DL, Almeida AL, Baldin VP, Caleffi-Ferracioli KR, Pavan FR. Rescue of susceptibility to second-line drugs in resistant clinical isolates of Mycobacterium tuberculosis. Future Microbiol 2022; 17:511-527. [PMID: 35317616 DOI: 10.2217/fmb-2021-0215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Antibiotic resistance is one of the biggest threats to global health, and this study aimed better understand how the efflux pumps are related to this process in tuberculosis clinical isolates. Results: The combination of antibiotics plus efflux pumps (EP) inhibitors was able to restore the susceptibility of clinical isolates in 100% of aminoglycosides resistance and 33.3% of the fluoroquinolones resistance. The relative expression of EP genes in pre-extensively drug-resistant isolates showed an increase of up to 1000-times. Conclusion: The rescue of susceptibility in the presence of EP inhibitors, the increased of activity and expression of the EP genes alert that the inhibition of EP can reduce the selection of resistant strains and improve treatment.
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Affiliation(s)
- Camila Maringolo-Ribeiro
- São Paulo State University (UNESP), School of Pharmaceutical Sciences, Tuberculosis Research Laboratory, Araraquara, São Paulo, Brazil
| | - Júlia A Grecco
- São Paulo State University (UNESP), School of Pharmaceutical Sciences, Tuberculosis Research Laboratory, Araraquara, São Paulo, Brazil
| | - Débora L Bellato
- São Paulo State University (UNESP), School of Pharmaceutical Sciences, Tuberculosis Research Laboratory, Araraquara, São Paulo, Brazil
| | - Aryadne L Almeida
- State University of Maringá (UEM), Department of Clinical Analysis & Biomedicine, Maringá, Paraná, Brazil
| | - Vanessa P Baldin
- State University of Maringá (UEM), Department of Clinical Analysis & Biomedicine, Maringá, Paraná, Brazil
| | | | - Fernando R Pavan
- São Paulo State University (UNESP), School of Pharmaceutical Sciences, Tuberculosis Research Laboratory, Araraquara, São Paulo, Brazil
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23
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Wang Y, Batra A, Schulenburg H, Dagan T. Gene sharing among plasmids and chromosomes reveals barriers for antibiotic resistance gene transfer. Philos Trans R Soc Lond B Biol Sci 2022; 377:20200467. [PMID: 34839702 PMCID: PMC8628082 DOI: 10.1098/rstb.2020.0467] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/18/2021] [Indexed: 01/21/2023] Open
Abstract
The emergence of antibiotic resistant bacteria is a major threat to modern medicine. Rapid adaptation to antibiotics is often mediated by the acquisition of plasmids carrying antibiotic resistance (ABR) genes. Nonetheless, the determinants of plasmid-mediated ABR gene transfer remain debated. Here, we show that the propensity of ABR gene transfer via plasmids is higher for accessory chromosomal ABR genes in comparison with core chromosomal ABR genes, regardless of the resistance mechanism. Analysing the pattern of ABR gene occurrence in the genomes of 2635 Enterobacteriaceae isolates, we find that 33% of the 416 ABR genes are shared between chromosomes and plasmids. Phylogenetic reconstruction of ABR genes occurring on both plasmids and chromosomes supports their evolution by lateral gene transfer. Furthermore, accessory ABR genes (encoded in less than 10% of the chromosomes) occur more abundantly in plasmids in comparison with core ABR genes (encoded in greater than or equal to 90% of the chromosomes). The pattern of ABR gene occurrence in plasmids and chromosomes is similar to that in the total Escherichia genome. Our results thus indicate that the previously recognized barriers for gene acquisition by lateral gene transfer apply also to ABR genes. We propose that the functional complexity of the underlying ABR mechanism is an important determinant of ABR gene transferability. This article is part of the theme issue 'The secret lives of microbial mobile genetic elements'.
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Affiliation(s)
- Yiqing Wang
- Institute of General Microbiology, Kiel University, Kiel, Germany
| | - Aditi Batra
- Zoological institute, Kiel University, Kiel, Germany
| | | | - Tal Dagan
- Institute of General Microbiology, Kiel University, Kiel, Germany
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24
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Ocular surface flora and prophylactic antibiotics for cataract surgery in the age of antimicrobial resistance. Jpn J Ophthalmol 2022; 66:111-118. [PMID: 35006494 DOI: 10.1007/s10384-021-00899-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 09/13/2021] [Indexed: 10/19/2022]
Abstract
According to the World Health Organization alert about the antimicrobial resistance crisis released in 2015, clinicians should strongly reconsider the prolonged use of antimicrobials. In this review, we focus on the ocular surface flora with respect to the trend of fluoroquinolone resistance, and its upset and restoration after topical administration of antimicrobials and preservatives. Even 3 weeks of topical administration of levofloxacin (LVFX) yields a selection of fluoroquinolone-resistant isolates bearing genetic changes in the ocular surface flora. One month of topical prophylactic administration of LVFX after cataract surgery induces the loss of diversity with LVFX-resistance of the ocular surface flora. Restoration of LVFX-sensitive flora occurs 6 to 9 months after the final topical administration of LVFX. The ocular surface flora recovers earlier in patients given LVFX for 1 week after the surgical procedure. These findings suggest that shorter periods of postoperative topical antibiotics are less frequently associated with persistent antimicrobial-resistant bacteria in the ocular flora. In addition, microbiologic analysis of ocular surfaces treated with a long period of eye drops containing benzalkonium chloride (BAC) showed a higher incidence of isolates resistant to methicillin and fluoroquinolones than did ocular surfaces treated with eye drops not containing BAC. To avoid the emergence of antimicrobial-resistant bacteria on the ocular surface, an urgent discussion must be held about the appropriate use of antibiotics and preservatives in the ophthalmology field.
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25
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Efflux-Mediated bile Resistance in Gram-Positive Pathogens. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2022. [DOI: 10.22207/jpam.16.1.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Gram-positive pathogens are causing many serious infections that affect humans and result in mild to severe diseases worldwide. In order to survive and initiate infection, enteric pathogens must resist the physiochemical defence factors in the human intestinal tract. One of these defence factors is bile, a potent antibacterial like compound in the intestine. Efflux pumps are the important mechanism by which bacteria resist antibacterial agents such as bile. Efflux of antimicrobial substances outside the bacterial cell is considered as a key factor for intestinal colonization and virulence of enteric pathogens. This paper will review the research conducted on efflux–mediated bile resistance in Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis and Clostridium perfringens. These bacteria colonize in the human & animal gastrointestinal tract and they have a multiple mechanism to resist the innate defences in the gut and antibacterial activity of bile. However, bile resistance in these bacteria is not fully understood. The evidence from this review suggests that Gram-positive pathogens have the ability to active transport of bile. Further research is needed to know how these pathogens sense bile and how bile regulates its virulence factor. In general, therefore, it seems that understanding the specific mechanism of bile resistance in enteric bacteria including gram-positive pathogens may involve in the development of novel strategies to control and treatment of gastrointestinal infections.
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26
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Zhu Y, Hao W, Wang X, Ouyang J, Deng X, Yu H, Wang Y. Antimicrobial peptides, conventional antibiotics, and their synergistic utility for the treatment of drug-resistant infections. Med Res Rev 2022; 42:1377-1422. [PMID: 34984699 DOI: 10.1002/med.21879] [Citation(s) in RCA: 123] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 12/09/2021] [Accepted: 12/23/2021] [Indexed: 12/13/2022]
Abstract
Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), are important effector immune defense molecules in multicellular organisms. AMPs exert their antimicrobial activities through several mechanisms; thus far, induction of drug resistance through AMPs has been regarded as unlikely. Therefore, they have great potential as new generation antimicrobial agents. To date, more than 30 AMP-related drugs are in the clinical trial phase. In recent years, studies show that some AMPs and conventional antibiotics have synergistic effects. The combined use of AMPs and antibiotics can kill drug-resistant pathogens, prevent drug resistance, and significantly improve the therapeutic effects of antibiotics. In this review, we discuss the progress in synergistic studies on AMPs and conventional antibiotics. An overview of the current understanding of the functional scope of AMPs, ongoing clinical trials, and challenges in the development processes are also presented.
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Affiliation(s)
- Yiyun Zhu
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Weijing Hao
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Xia Wang
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Jianhong Ouyang
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Xinyi Deng
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Haining Yu
- Department of Bioscience and Biotechnology, Dalian University of Technology, Dalian, Liaoning, China
| | - Yipeng Wang
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
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Webber A, Ratnaweera M, Harris A, Luisi BF, Ntsogo Enguéné VY. A Model for Allosteric Communication in Drug Transport by the AcrAB-TolC Tripartite Efflux Pump. Antibiotics (Basel) 2022; 11:52. [PMID: 35052929 PMCID: PMC8773123 DOI: 10.3390/antibiotics11010052] [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: 11/29/2021] [Revised: 12/22/2021] [Accepted: 12/28/2021] [Indexed: 01/30/2023] Open
Abstract
RND family efflux pumps are complex macromolecular machines involved in multidrug resistance by extruding antibiotics from the cell. While structural studies and molecular dynamics simulations have provided insights into the architecture and conformational states of the pumps, the path followed by conformational changes from the inner membrane protein (IMP) to the periplasmic membrane fusion protein (MFP) and to the outer membrane protein (OMP) in tripartite efflux assemblies is not fully understood. Here, we investigated AcrAB-TolC efflux pump's allostery by comparing resting and transport states using difference distance matrices supplemented with evolutionary couplings data and buried surface area measurements. Our analysis indicated that substrate binding by the IMP triggers quaternary level conformational changes in the MFP, which induce OMP to switch from the closed state to the open state, accompanied by a considerable increase in the interface area between the MFP subunits and between the OMPs and MFPs. This suggests that the pump's transport-ready state is at a more favourable energy level than the resting state, but raises the puzzle of how the pump does not become stably trapped in a transport-intermediate state. We propose a model for pump allostery that includes a downhill energetic transition process from a proposed 'activated' transport state back to the resting pump.
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Affiliation(s)
- Anya Webber
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK; (A.W.); (A.H.)
| | - Malitha Ratnaweera
- Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK;
| | - Andrzej Harris
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK; (A.W.); (A.H.)
| | - Ben F. Luisi
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK; (A.W.); (A.H.)
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Abd El-Aleam RH, George RF, Georgey HH, Abdel-Rahman HM. Bacterial virulence factors: a target for heterocyclic compounds to combat bacterial resistance. RSC Adv 2021; 11:36459-36482. [PMID: 35494393 PMCID: PMC9043591 DOI: 10.1039/d1ra06238g] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/01/2021] [Indexed: 12/17/2022] Open
Abstract
Antibiotic resistance is one of the most important challenges of the 21st century. However, the growing understanding of bacterial pathogenesis and cell-to-cell communication has revealed many potential strategies for the discovery of drugs that can be used for the treatment of bacterial infections. Interfering with bacterial virulence and/or quorum sensing could be a particularly interesting approach, because it is believed to exert less selective pressure on the bacterial resistance than with traditional strategies, geared toward killing bacteria or preventing their growth. Here, we discuss the mechanism of bacterial virulence, presenting promising strategies and recently synthesized heterocyclic compounds to combat future bacterial infections.
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Affiliation(s)
- Rehab H Abd El-Aleam
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information MTI Cairo 11571 Egypt
| | - Riham F George
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University Cairo 11562 Egypt
| | - Hanan H Georgey
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University Cairo 11562 Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University Cairo 11786 Egypt
| | - Hamdy M Abdel-Rahman
- Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University Assiut 71526 Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University Beni Suef Egypt
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29
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Wang Z, Li H, Zhang J, Wang X, Zhang Y, Wang H. Identification of a novel plasmid-mediated tigecycline resistance-related gene, tet(Y), in Acinetobacter baumannii. J Antimicrob Chemother 2021; 77:58-68. [PMID: 34634801 DOI: 10.1093/jac/dkab375] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/20/2021] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES To characterize a novel plasmid-mediated tigecycline resistance-related gene, tet(Y), in a clinical Acinetobacter baumannii isolate from China. METHODS The tet(Y)-encoded tigecycline-resistant A. baumannii 2016GDAB1 was screened through antimicrobial susceptibility testing and WGS. The function of tet(Y) was verified by complementation of tet(Y). The plasmid transferability and stability were detected via plasmid conjugation and in vitro bacterial passaging. The 3D structure of Tet(Y) was predicted and docked using tFold and AutoDock Vina. RESULTS The tigecycline-resistant A. baumannii 2016GDAB1 was isolated from bronchoalveolar lavage fluid of a patient with hospital-acquired pneumonia. However, this strain did not harbour any common tigecycline resistance genes, determinants or mutations. 2016GDAB1 belongs to the non-epidemic clone ST355 (Oxford scheme), which has been mainly reported in animals. The tet(Y) gene was located on a 72 156 bp plasmid and genomic environment analysis revealed that Tn5393 may play a role in tet(Y) transmission, whereas phylogenetic analysis indicated the origin of tet(Y) as from Aeromonas. Overexpression of tet(Y) resulted in a 2- to 4-fold increase in tigecycline MIC. Introduction of the tet(Y)-harbouring plasmid p2016GDAB1 via electroporation resulted in a 16-fold increase in tigecycline MIC but failed to transfer into the tigecycline-susceptible A. baumannii recipient via conjugation. Isolates carrying the tet(Y) gene were vulnerable to tigecycline pressure and exhibited decreased susceptibility to tigecycline. A tet(Y)-carrying plasmid was stably maintained in the host strains. CONCLUSIONS This study identified the tigecycline resistance-related gene tet(Y) in A. baumannii. This gene conferred an increased tigecycline MIC and the transposable element Tn5393 may play a role in its transmission across isolates.
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Affiliation(s)
- Zhiren Wang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Henan Li
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Jiangang Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Xiaojuan Wang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Yawei Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Hui Wang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
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30
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Mohanty H, Pachpute S, Yadav RP. Mechanism of drug resistance in bacteria: efflux pump modulation for designing of new antibiotic enhancers. Folia Microbiol (Praha) 2021; 66:727-739. [PMID: 34431062 DOI: 10.1007/s12223-021-00910-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 08/10/2021] [Indexed: 11/21/2022]
Abstract
Drug resistance has now become a serious concern in the domain of microbial infection. Bacteria are becoming smarter by displaying a variety of mechanisms during drug resistance. It is not only helping bacteria to adapt nicely in adverse environment but it also makes a smart system for better availability of nutritional status for microorganisms. In this domain, pathogenic bacteria are extensively studied and their mechanism for drug resistance is well explored. The common modes in bacterial resistance include degradation of antibiotics by enzymes, antibiotic target modification or inactivation by enzymatic actions, complete replacement of antibiotic targets, quorum sensing (QS) mechanism, and efflux pump-based extrusion of antibiotics. In this review, various mechanisms of drug resistance in bacteria have been highlighted with giving the importance of efflux pumps. This can be explored as a knowledge source for the management of a variety of bacterial infections, related disease and vibrant clue for next-generation drug development.
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Affiliation(s)
- Harshita Mohanty
- MGMIHS OMICS Research Center, MGM Central Research Laboratory, MGM Medical College and Hospital, MGM Institute of Health Sciences, Sector 1, Kamothe, Navi Mumbai-410209, Maharashtra, India.,Department of Molecular Biology, MGM School of Biomedical Sciences, MGM Institute of Health Sciences, Sector 1, Kamothe, Navi Mumbai-410209, Maharashtra, India
| | - Samir Pachpute
- Department of Medical Microbiology, MGM Medical College and Hospital, MGM Institute of Health Sciences, Sector 1, Kamothe, Navi Mumbai-410209, Maharashtra, India
| | - Raman P Yadav
- MGMIHS OMICS Research Center, MGM Central Research Laboratory, MGM Medical College and Hospital, MGM Institute of Health Sciences, Sector 1, Kamothe, Navi Mumbai-410209, Maharashtra, India. .,Department of Molecular Biology, MGM School of Biomedical Sciences, MGM Institute of Health Sciences, Sector 1, Kamothe, Navi Mumbai-410209, Maharashtra, India.
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31
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Tatay-Dualde J, Prats-van der Ham M, Gaurivaud P, de la Fe C, Tardy F. Efflux Might Participate in Decreased Susceptibility to Oxytetracycline in Contagious Agalactia-Causative Mycoplasma spp. Animals (Basel) 2021; 11:ani11082449. [PMID: 34438907 PMCID: PMC8388784 DOI: 10.3390/ani11082449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 11/16/2022] Open
Abstract
Contagious agalactia is associated with mastitis, keratoconjunctivitis, arthritis, pneumonia, and septicemia in small ruminants in countries with large dairy industries worldwide. The causative agents belong to four (sub)species of the Mycoplasma genus that have remained essentially susceptible to antimicrobials, including to the widely-used tetracycline family. However, some clinical isolates have been detected that show increased minimum inhibitory concentrations of tetracyclines, although they do not harbor the mutation in the 16SrRNA gene usually associated with resistance. The present work aimed to assess whether efflux pumps, infrequently described in mycoplasmas, could participate in the observed moderate loss of susceptibility. General efflux mechanisms were measured (i) using the fluorescence property of ethidium bromide when accumulated intracellularly and intercalated in the mycoplasma genomes, its active extrusion resulting in a temperature-dependent decrease in fluorescence and (ii) monitoring the growth inhibition of mycoplasmas by subinhibitory concentrations of tetracycline with or without reserpine, a known inhibitor of efflux in other bacteria. Both methods revealed non-specific efflux phenomena in most of the isolates tested, although their efficacy was difficult to quantify. This property could contribute to the acquisition of mutations conferring resistance by maintaining intracellular concentrations of tetracyclines at subinhibitory levels.
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Affiliation(s)
- Juan Tatay-Dualde
- Ruminant Health Research Group, Faculty of Veterinary Sciences, Regional Campus of International Excellence “Campus Mare Nostrum”, Campus de Espinardo s/n, University of Murcia, 30100 Murcia, Spain; (J.T.-D.); (M.P.-v.d.H.); (C.d.l.F.)
| | - Miranda Prats-van der Ham
- Ruminant Health Research Group, Faculty of Veterinary Sciences, Regional Campus of International Excellence “Campus Mare Nostrum”, Campus de Espinardo s/n, University of Murcia, 30100 Murcia, Spain; (J.T.-D.); (M.P.-v.d.H.); (C.d.l.F.)
| | - Patrice Gaurivaud
- UMR Mycoplasmoses Animales, Anses, VetAgro Sup, Université de Lyon, F-69364 Lyon, France;
| | - Christian de la Fe
- Ruminant Health Research Group, Faculty of Veterinary Sciences, Regional Campus of International Excellence “Campus Mare Nostrum”, Campus de Espinardo s/n, University of Murcia, 30100 Murcia, Spain; (J.T.-D.); (M.P.-v.d.H.); (C.d.l.F.)
| | - Florence Tardy
- UMR Mycoplasmoses Animales, Anses, VetAgro Sup, Université de Lyon, F-69364 Lyon, France;
- Correspondence: ; Tel.: +33-4-78696843
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32
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Jubair N, Rajagopal M, Chinnappan S, Abdullah NB, Fatima A. Review on the Antibacterial Mechanism of Plant-Derived Compounds against Multidrug-Resistant Bacteria (MDR). EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:3663315. [PMID: 34447454 PMCID: PMC8384518 DOI: 10.1155/2021/3663315] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/27/2021] [Accepted: 07/24/2021] [Indexed: 02/06/2023]
Abstract
Microbial resistance has progressed rapidly and is becoming the leading cause of death globally. The spread of antibiotic-resistant microorganisms has been a significant threat to the successful therapy against microbial infections. Scientists have become more concerned about the possibility of a return to the pre-antibiotic era. Thus, searching for alternatives to fight microorganisms has become a necessity. Some bacteria are naturally resistant to antibiotics, while others acquire resistance mainly by the misuse of antibiotics and the emergence of new resistant variants through mutation. Since ancient times, plants represent the leading source of drugs and alternative medicine for fighting against diseases. Plants are rich sources of valuable secondary metabolites, such as alkaloids, quinones, tannins, terpenoids, flavonoids, and polyphenols. Many studies focus on plant secondary metabolites as a potential source for antibiotic discovery. They have the required structural properties and can act by different mechanisms. This review analyses the antibiotic resistance strategies produced by multidrug-resistant bacteria and explores the phytochemicals from different classes with documented antimicrobial action against resistant bacteria, either alone or in combination with traditional antibiotics.
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Affiliation(s)
- Najwan Jubair
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Mogana Rajagopal
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Sasikala Chinnappan
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | | | - Ayesha Fatima
- Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul, Turkey
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Pasqua M, Bonaccorsi di Patti MC, Fanelli G, Utsumi R, Eguchi Y, Trirocco R, Prosseda G, Grossi M, Colonna B. Host - Bacterial Pathogen Communication: The Wily Role of the Multidrug Efflux Pumps of the MFS Family. Front Mol Biosci 2021; 8:723274. [PMID: 34381818 PMCID: PMC8350985 DOI: 10.3389/fmolb.2021.723274] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/13/2021] [Indexed: 12/23/2022] Open
Abstract
Bacterial pathogens are able to survive within diverse habitats. The dynamic adaptation to the surroundings depends on their ability to sense environmental variations and to respond in an appropriate manner. This involves, among others, the activation of various cell-to-cell communication strategies. The capability of the bacterial cells to rapidly and co-ordinately set up an interplay with the host cells and/or with other bacteria facilitates their survival in the new niche. Efflux pumps are ubiquitous transmembrane transporters, able to extrude a large set of different molecules. They are strongly implicated in antibiotic resistance since they are able to efficiently expel most of the clinically relevant antibiotics from the bacterial cytoplasm. Besides antibiotic resistance, multidrug efflux pumps take part in several important processes of bacterial cell physiology, including cell to cell communication, and contribute to increase the virulence potential of several bacterial pathogens. Here, we focus on the structural and functional role of multidrug efflux pumps belonging to the Major Facilitator Superfamily (MFS), the largest family of transporters, highlighting their involvement in the colonization of host cells, in virulence and in biofilm formation. We will offer an overview on how MFS multidrug transporters contribute to bacterial survival, adaptation and pathogenicity through the export of diverse molecules. This will be done by presenting the functions of several relevant MFS multidrug efflux pumps in human life-threatening bacterial pathogens as Staphylococcus aureus, Listeria monocytogenes, Klebsiella pneumoniae, Shigella/E. coli, Acinetobacter baumannii.
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Affiliation(s)
- Martina Pasqua
- Department of Biology and Biotechnology "C. Darwin", Istituto Pasteur Italia, Sapienza Università di Roma, Rome, Italy
| | | | - Giulia Fanelli
- Department of Biology and Biotechnology "C. Darwin", Istituto Pasteur Italia, Sapienza Università di Roma, Rome, Italy
| | - Ryutaro Utsumi
- The Institute of Scientific and Industrial Research (SANKEN), Osaka University, Osaka, Japan
| | - Yoko Eguchi
- Department of Science and Technology on Food Safety, Kindai University, Kinokawa, Japan
| | - Rita Trirocco
- Department of Biology and Biotechnology "C. Darwin", Istituto Pasteur Italia, Sapienza Università di Roma, Rome, Italy
| | - Gianni Prosseda
- Department of Biology and Biotechnology "C. Darwin", Istituto Pasteur Italia, Sapienza Università di Roma, Rome, Italy
| | - Milena Grossi
- Department of Biology and Biotechnology "C. Darwin", Istituto Pasteur Italia, Sapienza Università di Roma, Rome, Italy
| | - Bianca Colonna
- Department of Biology and Biotechnology "C. Darwin", Istituto Pasteur Italia, Sapienza Università di Roma, Rome, Italy
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Sumyk M, Himpich S, Foong WE, Herrmann A, Pos KM, Tam HK. Binding of Tetracyclines to Acinetobacter baumannii TetR Involves Two Arginines as Specificity Determinants. Front Microbiol 2021; 12:711158. [PMID: 34349752 PMCID: PMC8326586 DOI: 10.3389/fmicb.2021.711158] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 06/23/2021] [Indexed: 11/13/2022] Open
Abstract
Acinetobacter baumannii is an important nosocomial pathogen that requires thoughtful consideration in the antibiotic prescription strategy due to its multidrug resistant phenotype. Tetracycline antibiotics have recently been re-administered as part of the combination antimicrobial regimens to treat infections caused by A. baumannii. We show that the TetA(G) efflux pump of A. baumannii AYE confers resistance to a variety of tetracyclines including the clinically important antibiotics doxycycline and minocycline, but not to tigecycline. Expression of tetA(G) gene is regulated by the TetR repressor of A. baumannii AYE (AbTetR). Thermal shift binding experiments revealed that AbTetR preferentially binds tetracyclines which carry a O-5H moiety in ring B, whereas tetracyclines with a 7-dimethylamino moiety in ring D are less well-recognized by AbTetR. Confoundingly, tigecycline binds to AbTetR even though it is not transported by TetA(G) efflux pump. Structural analysis of the minocycline-bound AbTetR-Gln116Ala variant suggested that the non-conserved Arg135 interacts with the ring D of minocycline by cation-π interaction, while the invariant Arg104 engages in H-bonding with the O-11H of minocycline. Interestingly, the Arg135Ala variant exhibited a binding preference for tetracyclines with an unmodified ring D. In contrast, the Arg104Ala variant preferred to bind tetracyclines which carry a O-6H moiety in ring C except for tigecycline. We propose that Arg104 and Arg135, which are embedded at the entrance of the AbTetR binding pocket, play important roles in the recognition of tetracyclines, and act as a barrier to prevent the release of tetracycline from its binding pocket upon AbTetR activation. The binding data and crystal structures obtained in this study might provide further insight for the development of new tetracycline antibiotics to evade the specific efflux resistance mechanism deployed by A. baumannii.
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Affiliation(s)
- Manuela Sumyk
- Institute of Biochemistry, Goethe-University Frankfurt, Frankfurt, Germany
| | - Stephanie Himpich
- Institute of Biochemistry, Goethe-University Frankfurt, Frankfurt, Germany
| | - Wuen Ee Foong
- Institute of Biochemistry, Goethe-University Frankfurt, Frankfurt, Germany
| | - Andrea Herrmann
- Institute of Biochemistry, Goethe-University Frankfurt, Frankfurt, Germany
| | - Klaas M Pos
- Institute of Biochemistry, Goethe-University Frankfurt, Frankfurt, Germany
| | - Heng-Keat Tam
- Institute of Biochemistry, Goethe-University Frankfurt, Frankfurt, Germany
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35
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Loza-Correa M, Yousuf B, Ramirez-Arcos S. Staphylococcus epidermidis undergoes global changes in gene expression during biofilm maturation in platelet concentrates. Transfusion 2021; 61:2146-2158. [PMID: 33904608 DOI: 10.1111/trf.16418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/31/2021] [Accepted: 03/31/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Staphylococcus epidermidis forms surface-attached aggregates (biofilms) when grown in platelet concentrates (PCs). Comparative transcriptome analyses were undertaken to investigate differential gene expression of S. epidermidis biofilms grown in PCs. STUDY DESIGN AND METHODS Two S. epidermidis strains isolated from human skin (AZ22 and AZ39) and one strain isolated from contaminated PCs (ST02) were grown in glucose-supplemented Trypticase Soy Broth (TSBg) and PCs. RNA was extracted and sequenced using Illumina HiSeq. Differential expression analysis was done using DESeq, and significantly differentially expressed genes (DEGs) were selected. DEGs were subjected to Kyoto encyclopedia of genes and genomes and Gene Ontology analyses. Differential gene expression was validated with quantitative reverse transcription-PCR. RESULTS A total of 436, 442, and 384 genes were expressed in AZ22, AZ39, and ST02, respectively. DEG analysis showed that 170, 172, and 117 genes were upregulated in PCs in comparison to TSBg, whereas 120, 135, and 89 genes were downregulated (p < .05) in mature biofilms of AZ22, AZ39, and ST02, respectively. Twenty-seven DEGs were shared by all three strains. While 76 DEGs were shared by AZ22 and AZ39, only 34 and 21 DEGs were common between ST02, and AZ22 and AZ39, respectively. Significant transcriptional expression changes were observed in genes involved in platelet-bacteria interaction, biofilm formation, production of virulence factors, and resistance to antimicrobial peptides and antibiotics. CONCLUSION Differential gene expression in S. epidermidis is triggered by the stressful PC storage environment. Upregulation of virulence and antimicrobial resistance genes could have clinical implications for transfusion patients.
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Affiliation(s)
- Maria Loza-Correa
- Centre for Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
| | - Basit Yousuf
- Centre for Innovation, Canadian Blood Services, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Sandra Ramirez-Arcos
- Centre for Innovation, Canadian Blood Services, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
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36
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Liu J, Wu P, Guo Q, Lai X, Ruan B, Wang H, Rehman S, Chen M. Kaolinite weakens the co-stress of ampicillin and tetracycline on Escherichia coli through multiple pathways. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:25228-25240. [PMID: 33453031 DOI: 10.1007/s11356-021-12356-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 01/02/2021] [Indexed: 06/12/2023]
Abstract
Ampicillin and tetracycline are common antibiotics and can threaten humans by inducing antibiotic resistance in bacteria. Microorganisms are usually exposed to a mixed antibiotic system in the environment. However, there are few researches on the specific regulatory mechanisms of clay on microorganisms under the stress of complex antibiotics. In this study, tandem mass tag-based coupled with two-dimensional liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) was employed to recognize and quantify changes in protein expression of Escherichia coli (E. coli) after culture for 15 days, with or without kaolinite in the co-stress of ampicillin and tetracycline. The results indicated that kaolinite could activate metabolic pathways of E. coli such as the energy metabolism, the biosynthesis of other secondary metabolites, and the metabolism of cofactors and vitamins. Particularly, the fatty acid degradation pathway has also been promoted, indicating that in the same unfavorable environment, kaolinite might influence the composition of E. coli cell membranes. This might be due to the change in membrane composition that was a kind of adaptive strategy of bacterial evolution. Moreover, kaolinite could promote multidrug efflux system to export the bacterial intracellular toxic substances, making E. coli survive better in an adverse environment. Consequently, this study not only disclosed the regulation of kaolinite on E. coli in a complex antibiotic environment but also provided new insights into the environmental process of antibiotic resistance.
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Affiliation(s)
- Juan Liu
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China
| | - Pingxiao Wu
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China.
- The Key Lab of Pollution Control and Ecosystem Restoration in Industry Clusters, Ministry of Education, Guangzhou, 510006, People's Republic of China.
- Guangdong Provincial Key Laboratory of Solid Wastes Pollution Control and Recycling, South China University of Technology, Guangzhou, 510006, People's Republic of China.
- Guangdong Provincial Engineering and Technology Research Center for Environmental Risk Prevention and Emergency Disposal, Guangzhou, 510006, People's Republic of China.
- Guangdong Engineering and Technology Research Center for Environmental Nanomaterials, Guangzhou, 510006, People's Republic of China.
| | - Qing Guo
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China
| | - Xiaolin Lai
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China
| | - Bo Ruan
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China
| | - Huimin Wang
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China
| | - Saeed Rehman
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China
| | - Meiqing Chen
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China
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37
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In Silico Approach for Phytocompound-Based Drug Designing to Fight Efflux Pump-Mediated Multidrug-Resistant Mycobacterium tuberculosis. Appl Biochem Biotechnol 2021; 193:1757-1779. [PMID: 33826064 PMCID: PMC8024441 DOI: 10.1007/s12010-021-03557-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/22/2021] [Indexed: 01/01/2023]
Abstract
Tuberculosis (TB), caused by the bacteria Mycobacterium tuberculosis, is one of the principal causes of death in the world despite the existence of a significant number of antibiotics aimed against it. This is mainly due to the drug resistance mechanisms present in the bacterium, which leads to multidrug-resistant tuberculosis (MDR-TB). Additionally, the development of new antibiotics has become limited over the years. Although there are various drug resistance mechanisms present, efflux pumps are of utmost importance because they extrude out several dissimilar antitubercular drugs out of the cell. There are many efflux pump proteins present in Mycobacterium tuberculosis. Therefore, blocking these efflux pumps by inhibitors can raise the efficacy of the existing antibiotics and may also pave the path for the discovery and synthesis of new drugs. Plant compounds can act as a resource for the development of efflux pump inhibitors (EPIs), which may eventually replace or augment the current therapeutic options. This is mainly because plants have been traditionally used for ages for food or treatment and are considered safe with little or no side effects. Various computational tools are available which are used for the virtual screening of a large number of phytocompounds within a short span of time. This review aims to highlight the mechanism and appearance of drug resistance in Mycobacterium tuberculosis with emphasis on efflux pumps along with the significance of phytochemicals as inhibitors of these pumps and their screening strategy by computational approaches.
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38
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Henderson PJF, Maher C, Elbourne LDH, Eijkelkamp BA, Paulsen IT, Hassan KA. Physiological Functions of Bacterial "Multidrug" Efflux Pumps. Chem Rev 2021; 121:5417-5478. [PMID: 33761243 DOI: 10.1021/acs.chemrev.0c01226] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bacterial multidrug efflux pumps have come to prominence in human and veterinary pathogenesis because they help bacteria protect themselves against the antimicrobials used to overcome their infections. However, it is increasingly realized that many, probably most, such pumps have physiological roles that are distinct from protection of bacteria against antimicrobials administered by humans. Here we undertake a broad survey of the proteins involved, allied to detailed examples of their evolution, energetics, structures, chemical recognition, and molecular mechanisms, together with the experimental strategies that enable rapid and economical progress in understanding their true physiological roles. Once these roles are established, the knowledge can be harnessed to design more effective drugs, improve existing microbial production of drugs for clinical practice and of feedstocks for commercial exploitation, and even develop more sustainable biological processes that avoid, for example, utilization of petroleum.
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Affiliation(s)
- Peter J F Henderson
- School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Claire Maher
- School of Environmental and Life Sciences, University of Newcastle, Callaghan 2308, New South Wales, Australia
| | - Liam D H Elbourne
- Department of Biomolecular Sciences, Macquarie University, Sydney 2109, New South Wales, Australia.,ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney 2019, New South Wales, Australia
| | - Bart A Eijkelkamp
- College of Science and Engineering, Flinders University, Bedford Park 5042, South Australia, Australia
| | - Ian T Paulsen
- Department of Biomolecular Sciences, Macquarie University, Sydney 2109, New South Wales, Australia.,ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney 2019, New South Wales, Australia
| | - Karl A Hassan
- School of Environmental and Life Sciences, University of Newcastle, Callaghan 2308, New South Wales, Australia.,ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney 2019, New South Wales, Australia
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39
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da Silva ACA, Matias EFF, Rocha JE, Araújo ACJD, de Freitas TS, Campina FF, Costa MDS, Silva LE, Amaral WD, Maia BHLNS, Ferriani AP, Bezerra CF, Iriti M, Coutinho HDM. Gas chromatography coupled to mass spectrometry (GC-MS) characterization and evaluation of antibacterial bioactivities of the essential oils from Piper arboreum Aubl., Piper aduncum L. e Piper gaudichaudianum Kunth. Z NATURFORSCH C 2021; 76:35-42. [PMID: 32673283 DOI: 10.1515/znc-2020-0045] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 05/29/2020] [Indexed: 11/15/2022]
Abstract
The objective of this study was to determine the chemical profile and to evaluate the antibacterial activity of the essential oils of Piper species and modulation of the antibiotic activity, using the microdilution method to determine the minimum inhibitory concentration. The chemical components were characterized by gas chromatography coupled to mass spectrometry, which revealed β-copaen-4-α-ol (31.38%), spathulenol (25.92%), and germacrene B (21.53%) as major constituents of the essential oils of Piper arboreum, Piper aduncum, and Piper gaudichaudianum, respectively. The essential oils analyzed in this study did not present a clinically relevant activity against standard and multiresistant Escherichia coli. However, in the case of multiresistant Staphylococcus aureus, there was a significant activity, corroborating with reports in the literature, where Gram-positive bacteria are more susceptible to antimicrobial activity. The essential oils modulated the effect of the antibiotics norfloxacin and gentamicin, having on the latter greater modulating effect; however, for erythromycin, no statistically significant effect was observed. In conclusion, the results obtained in this study demonstrated that the essential oils of the analyzed Piper species present an inhibitory effect against S. aureus and modulate antibiotic activity, most of which presents synergistic activity.
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Affiliation(s)
| | | | | | | | | | | | | | - Luiz E Silva
- Federal University of Paraná (UFPR), Curitiba, PR, Brazil
| | | | | | | | | | - Marcello Iriti
- Departement of Agricultural and Environmental Sciences, Milan State University20133, Milan, Italy
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40
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Wang X, Wei J, Xiao Y, Luan S, Ning X, Bai L. Efflux identification and engineering for ansamitocin P-3 production in Actinosynnema pretiosum. Appl Microbiol Biotechnol 2021; 105:695-706. [PMID: 33394151 DOI: 10.1007/s00253-020-11044-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 11/25/2020] [Accepted: 12/06/2020] [Indexed: 12/31/2022]
Abstract
Ansamitocin P-3 (AP-3) exhibits potent biological activities against various tumor cells. As an important drug precursor, reliable supply of AP-3 is limited by low fermentation yield. Although different strategies have been implemented to improve AP-3 yield, few have investigated the impact of efflux on AP-3 production. In this study, AP-3 efflux genes were identified through combined analysis of two sets of transcriptomes. The production-based transcriptome was implemented to search for efflux genes highly expressed in response to AP-3 accumulation during the fermentation process, while the resistance-based transcriptome was designed to screen for genes actively expressed in response to the exogenous supplementation of AP-3. After comprehensive analysis of two transcriptomes, six efflux genes outside the ansamitocin BGC were identified. Among the six genes, individual deletion of APASM_2704, APASM_6861, APASM_3193, and APASM_2805 resulted in decreased AP-3 production, and alternative overexpression led to AP-3 yield increase from 264.6 to 302.4, 320.4, 330.6, and 320.6 mg/L, respectively. Surprisingly, APASM_2704 was found to be responsible for exportation of AP-3 and another macro-lactam antibiotic pretilactam. Furthermore, growth of APASM_2704, APASM_3193, or APASM_2805 overexpression mutants was obviously improved under 300 mg/L AP-3 supplementation. In summary, our study has identified AP-3 efflux genes outside the ansamitocin BGC by comparative transcriptomic analysis, and has shown that enhancing the transcription of transporter genes can improve AP-3 production, shedding light on strategies used for exporter screening and antibiotic production improvement. KEY POINTS: • AP-3-related efflux genes were identified by transcriptomic analysis. • Deletion of the identified efflux genes led in AP-3 yield decrease. • Overexpression of the efflux genes resulted in increased AP-3 production.
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Affiliation(s)
- Xinran Wang
- Center for Synthetic Biochemistry, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes for Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. .,State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
| | - Jianhua Wei
- State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Yifan Xiao
- State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Shuhui Luan
- State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Xinjuan Ning
- State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Linquan Bai
- State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
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41
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Ordikhani F, Zandi N, Mazaheri M, Luther GA, Ghovvati M, Akbarzadeh A, Annabi N. Targeted nanomedicines for the treatment of bone disease and regeneration. Med Res Rev 2020; 41:1221-1254. [PMID: 33347711 DOI: 10.1002/med.21759] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 10/14/2020] [Accepted: 11/11/2020] [Indexed: 12/17/2022]
Abstract
Targeted delivery by either passive or active targeting of therapeutics to the bone is an attractive treatment for various bone related diseases such as osteoporosis, osteosarcoma, multiple myeloma, and metastatic bone tumors. Engineering novel drug delivery carriers can increase therapeutic efficacy and minimize the risk of side effects. Developmnet of nanocarrier delivery systems is an interesting field of ongoing studies with opportunities to provide more effective therapies. In addition, preclinical nanomedicine research can open new opportunities for preclinical bone-targeted drug delivery; nevertheless, further research is needed to progress these therapies towards clinical applications. In the present review, the latest advancements in targeting moieties and nanocarrier drug delivery systems for the treatment of bone diseases are summarized. We also review the regeneration capability and effective delivery of nanomedicines for orthopedic applications.
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Affiliation(s)
- Farideh Ordikhani
- Transplantation Research Center, Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nooshin Zandi
- Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran, Iran.,Department of Chemical Engineering, Northeastern University, Boston, Massachusetts, USA
| | - Mozhdeh Mazaheri
- Department of Materials Science and Engineering, Sharif University of Technology, Tehran, Iran
| | - Gaurav A Luther
- Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mahsa Ghovvati
- Department of Chemical and Biomolecular Engineering, University of California- Los Angeles, California, Los Angeles, USA
| | - Abolfazl Akbarzadeh
- Department of Chemical Engineering, Northeastern University, Boston, Massachusetts, USA.,Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasim Annabi
- Department of Chemical and Biomolecular Engineering, University of California- Los Angeles, California, Los Angeles, USA
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42
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Heinzinger LR, Johnson A, Wurster JI, Nilson R, Penumutchu S, Belenky P. Oxygen and Metabolism: Digesting Determinants of Antibiotic Susceptibility in the Gut. iScience 2020; 23:101875. [PMID: 33354661 PMCID: PMC7744946 DOI: 10.1016/j.isci.2020.101875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Microbial metabolism is a major determinant of antibiotic susceptibility. Environmental conditions that modify metabolism, notably oxygen availability and redox potential, can directly fine-tune susceptibility to antibiotics. Despite this, relatively few studies have discussed these modifications within the gastrointestinal tract and their implication on in vivo drug activity and the off-target effects of antibiotics in the gut. In this review, we discuss the environmental and biogeographical complexity of the gastrointestinal tract in regard to oxygen availability and redox potential, addressing how the heterogeneity of gut microhabitats may modify antibiotic activity in vivo. We contextualize the current literature surrounding oxygen availability and antibiotic efficacy and discuss empirical treatments. We end by discussing predicted patterns of antibiotic activity in prominent microbiome taxa, given gut heterogeneity, oxygen availability, and polymicrobial interactions. We also propose additional work required to fully elucidate the role of oxygen metabolism on antibiotic susceptibility in the context of the gut.
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Affiliation(s)
- Lauren R. Heinzinger
- Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA
| | - Angus Johnson
- Department of Biological Science, Binghamton University, Binghamton, NY 13902, USA
| | - Jenna I. Wurster
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA
| | - Rachael Nilson
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA
| | - Swathi Penumutchu
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA
| | - Peter Belenky
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA
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43
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Rolta R, Salaria D, Kumar V, Patel CN, Sourirajan A, Baumler DJ, Dev K. Molecular docking studies of phytocompounds of Rheum emodi Wall with proteins responsible for antibiotic resistance in bacterial and fungal pathogens: in silico approach to enhance the bio-availability of antibiotics. J Biomol Struct Dyn 2020; 40:3789-3803. [PMID: 33225862 DOI: 10.1080/07391102.2020.1850364] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Rheum emodi Wall. (Himalayan rhubarb) has many pharmacological activities such as antioxidant, antimicrobial, antiviral, anticancer and wound healing. The present study was aimed to understand if major phytocompounds of Rheum emodi could bind proteins responsible for antibiotic resistance in bacterial and fungal pathogens and enhance the potency of antibiotics. The major phytocompounds of R. emodi (emodin, rhein-13c6 and chrysophenol dimethy ether) were retrieved from the Pubchem and target proteins were retrieved from RCSB protein data bank. The docking study was performed by using AutoDock vina software and Molinspiration, swiss ADME servers were used for the determination of Lipinski rule of 5, drug-likeness prediction respectively, whereas, admetSAR and Protox-II tools were used for toxicity prediction. To study the docking accuracy of protein-ligand complexes, MD simulation for 100 ns was done by using Desmond program version 2.0 (Academic version). Among all the selected phytocompounds, emodin showed the best binding affinity against bacterial (Penicillin binding protein 3, 3VSL and fungal target (cytochrome P450 14 alpha-sterol demethylase 1EA1) with binding energy -8.2 and -8.0 Kcal mol-1 respectively. Similarly, rhein-13C6 showed the best binding affinity against fungal target (n-myristoyl transferase 1IYL) with binding energy -8.0 Kcal mol-1 which is higher than antibacterial and antifungal antibiotics. All the selected phytocompounds also fulfill Lipinski rule, non-carcinogenic and non-cytotoxic in nature. These compounds also showed high LD50 value showing non-toxicity of these phytocompounds. MD simulation studies of phytocompounds (emodin and rhein-13C6) define the stability of protein-ligand complexes with in 100 ns time scale.Communicated by Freddie R. Salsbury.
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Affiliation(s)
- Rajan Rolta
- Faculty of Applied sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, District Solan, Himachal Pradesh, India
| | - Deeksha Salaria
- Faculty of Applied sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, District Solan, Himachal Pradesh, India
| | - Vikas Kumar
- Faculty of Applied sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, District Solan, Himachal Pradesh, India
| | - Chirag N Patel
- Department of Botany, Bioinformatics and Climate Change Impacts Management, University School of Science, Gujarat University, Ahmedabad, India
| | - Anuradha Sourirajan
- Faculty of Applied sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, District Solan, Himachal Pradesh, India
| | - David J Baumler
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN, USA
| | - Kamal Dev
- Faculty of Applied sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, District Solan, Himachal Pradesh, India
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44
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North OI, Brown ED. Phage-antibiotic combinations: a promising approach to constrain resistance evolution in bacteria. Ann N Y Acad Sci 2020; 1496:23-34. [PMID: 33175408 DOI: 10.1111/nyas.14533] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/15/2020] [Accepted: 10/26/2020] [Indexed: 12/18/2022]
Abstract
Antibiotic resistance has reached dangerously high levels throughout the world. A growing number of bacteria pose an urgent, serious, and concerning threat to public health. Few new antibiotics are available to clinicians and only few are in development, highlighting the need for new strategies to overcome the antibiotic resistance crisis. Combining existing antibiotics with phages, viruses the infect bacteria, is an attractive and promising alternative to standalone therapies. Phage-antibiotic combinations have been shown to suppress the emergence of resistance in bacteria, and sometimes even reverse it. Here, we discuss the mechanisms by which phage-antibiotic combinations reduce resistance evolution, and the potential limitations these mechanisms have in steering microbial resistance evolution in a desirable direction. We also emphasize the importance of gaining a better understanding of mechanisms behind physiological and evolutionary phage-antibiotic interactions in complex in-patient environments.
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Affiliation(s)
- Olesia I North
- Department of Biochemistry and Biomedical Sciences and M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Ontario, Canada
| | - Eric D Brown
- Department of Biochemistry and Biomedical Sciences and M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Ontario, Canada
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45
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Teelucksingh T, Thompson LK, Cox G. The Evolutionary Conservation of Escherichia coli Drug Efflux Pumps Supports Physiological Functions. J Bacteriol 2020; 202:e00367-20. [PMID: 32839176 PMCID: PMC7585057 DOI: 10.1128/jb.00367-20] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Bacteria harness an impressive repertoire of resistance mechanisms to evade the inhibitory action of antibiotics. One such mechanism involves efflux pump-mediated extrusion of drugs from the bacterial cell, which significantly contributes to multidrug resistance. Intriguingly, most drug efflux pumps are chromosomally encoded components of the intrinsic antibiotic resistome. In addition, in terms of xenobiotic detoxification, bacterial efflux systems often exhibit significant levels of functional redundancy. Efflux pumps are also considered to be highly conserved; however, the extent of conservation in many bacterial species has not been reported and the majority of genes that encode efflux pumps appear to be dispensable for growth. These observations, in combination with an increasing body of experimental evidence, imply alternative roles in bacterial physiology. Indeed, the ability of efflux pumps to facilitate antibiotic resistance could be a fortuitous by-product of ancient physiological functions. Using Escherichia coli as a model organism, we here evaluated the evolutionary conservation of drug efflux pumps and we provide phylogenetic analysis of the major efflux families. We show the E. coli drug efflux system has remained relatively stable and the majority (∼80%) of pumps are encoded in the core genome. This analysis further supports the importance of drug efflux pumps in E. coli physiology. In this review, we also provide an update on the roles of drug efflux pumps in the detoxification of endogenously synthesized substrates and pH homeostasis. Overall, gaining insight into drug efflux pump conservation, common evolutionary ancestors, and physiological functions could enable strategies to combat these intrinsic and ancient elements.
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Affiliation(s)
- Tanisha Teelucksingh
- College of Biological Sciences, Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada
| | - Laura K Thompson
- College of Biological Sciences, Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada
| | - Georgina Cox
- College of Biological Sciences, Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada
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46
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Reuter A, Virolle C, Goldlust K, Berne-Dedieu A, Nolivos S, Lesterlin C. Direct visualisation of drug-efflux in liveEscherichia colicells. FEMS Microbiol Rev 2020; 44:782-792. [DOI: 10.1093/femsre/fuaa031] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 07/22/2020] [Indexed: 12/13/2022] Open
Abstract
ABSTRACTDrug-efflux by pump proteins is one of the major mechanisms of antibiotic resistance in bacteria. Here, we use quantitative fluorescence microscopy to investigate the real-time dynamics of drug accumulation and efflux in live E. coli cells. We visualize simultaneously the intrinsically fluorescent protein-synthesis inhibitor tetracycline (Tc) and the fluorescently labelled Tc-specific efflux pump, TetA. We show that Tc penetrates the cells within minutes and accumulates to stable intracellular concentration after ∼20 min. The final level of drug accumulation reflects the balance between Tc-uptake by the cells and Tc-efflux by pump proteins. In wild-type Tc-sensitive cells, drug accumulation is significantly limited by the activity of the multidrug efflux pump, AcrAB-TolC. Tc-resistance wild-type cells carrying a plasmid-borne Tn10 transposon contain variable amounts of TetA protein, produced under steady-state repression by the TetR repressor. TetA content heterogeneity determines the cells’ initial ability to efflux Tc. Yet, efflux remains partial until the synthesis of additional TetA pumps allows for Tc-efflux activity to surpass Tc-uptake. Cells overproducing TetA no longer accumulate Tc and become resistant to high concentrations of the drug. This work uncovers the dynamic balance between drug entry, protein-synthesis inhibition, efflux-pump production, drug-efflux activity and drug-resistance levels.
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Affiliation(s)
- Audrey Reuter
- Microbiologie Moléculaire et Biochimie Structurale (MMSB), Université Lyon 1, CNRS, Inserm, UMR5086, 69007, Lyon, France
| | - Chloé Virolle
- Microbiologie Moléculaire et Biochimie Structurale (MMSB), Université Lyon 1, CNRS, Inserm, UMR5086, 69007, Lyon, France
| | - Kelly Goldlust
- Microbiologie Moléculaire et Biochimie Structurale (MMSB), Université Lyon 1, CNRS, Inserm, UMR5086, 69007, Lyon, France
| | - Annick Berne-Dedieu
- Microbiologie Moléculaire et Biochimie Structurale (MMSB), Université Lyon 1, CNRS, Inserm, UMR5086, 69007, Lyon, France
| | - Sophie Nolivos
- Microbiologie Moléculaire et Biochimie Structurale (MMSB), Université Lyon 1, CNRS, Inserm, UMR5086, 69007, Lyon, France
| | - Christian Lesterlin
- Microbiologie Moléculaire et Biochimie Structurale (MMSB), Université Lyon 1, CNRS, Inserm, UMR5086, 69007, Lyon, France
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Deshpande D, Magombedze G, Srivastava S, Bendet P, Lee PS, Cirrincione KN, Martin KR, Dheda K, Gumbo T. Once-a-week tigecycline for the treatment of drug-resistant TB. J Antimicrob Chemother 2020; 74:1607-1617. [PMID: 30820554 DOI: 10.1093/jac/dkz061] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/17/2019] [Accepted: 01/22/2019] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND MDR-TB and XDR-TB have poor outcomes. OBJECTIVES To examine the efficacy of tigecycline monotherapy in the hollow fibre system model of TB. METHODS We performed pharmacokinetic/pharmacodynamic studies using tigecycline human-like concentration-time profiles in the hollow fibre system model of TB in five separate experiments using Mycobacterium tuberculosis in log-phase growth or as semi-dormant or intracellular bacilli, as monotherapy. We also compared efficacy with the isoniazid/rifampicin/pyrazinamide combination (standard therapy). We then applied extinction mathematics, morphisms and Latin hypercube sampling to identify duration of therapy with tigecycline monotherapy. RESULTS The median tigecycline MIC for 30 M. tuberculosis clinical and laboratory isolates (67% MDR/XDR) was 2 mg/L. Tigecycline monotherapy was highly effective in killing M. tuberculosis in log-phase-growth and semi-dormant and intracellular M. tuberculosis. Once-a-week dosing had the same efficacy as daily therapy for the same cumulative dose; thus, tigecycline efficacy was linked to the AUC0-24/MIC ratio. Tigecycline replacement by daily minocycline after 4 weeks of therapy was effective in sterilizing bacilli. The AUC0-24/MIC ratio associated with optimal kill was 42.3. Tigecycline monotherapy had a maximum sterilizing effect (day 0 minus day 28) of 3.06 ± 0.20 log10 cfu/mL (r2 = 0.92) compared with 3.92 ± 0.45 log10 cfu/mL (r2 = 0.80) with optimized standard therapy. In our modelling, at a tigecycline monotherapy duration of 12 months, the proportion of patients with XDR-TB who reached bacterial population extinction was 64.51%. CONCLUSIONS Tigecycline could cure patients with XDR-TB or MDR-TB who have failed recommended therapy. Once-a-week tigecycline could also replace second-line injectables in MDR-TB regimens.
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Affiliation(s)
- Devyani Deshpande
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Gesham Magombedze
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Shashikant Srivastava
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Paula Bendet
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Pooi S Lee
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Kayle N Cirrincione
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Katherine R Martin
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Keertan Dheda
- Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Observatory, South Africa
| | - Tawanda Gumbo
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.,Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Observatory, South Africa
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48
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Lukačišinová M, Fernando B, Bollenbach T. Highly parallel lab evolution reveals that epistasis can curb the evolution of antibiotic resistance. Nat Commun 2020; 11:3105. [PMID: 32561723 PMCID: PMC7305214 DOI: 10.1038/s41467-020-16932-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/01/2020] [Indexed: 12/12/2022] Open
Abstract
Genetic perturbations that affect bacterial resistance to antibiotics have been characterized genome-wide, but how do such perturbations interact with subsequent evolutionary adaptation to the drug? Here, we show that strong epistasis between resistance mutations and systematically identified genes can be exploited to control spontaneous resistance evolution. We evolved hundreds of Escherichia coli K-12 mutant populations in parallel, using a robotic platform that tightly controls population size and selection pressure. We find a global diminishing-returns epistasis pattern: strains that are initially more sensitive generally undergo larger resistance gains. However, some gene deletion strains deviate from this general trend and curtail the evolvability of resistance, including deletions of genes for membrane transport, LPS biosynthesis, and chaperones. Deletions of efflux pump genes force evolution on inferior mutational paths, not explored in the wild type, and some of these essentially block resistance evolution. This effect is due to strong negative epistasis with resistance mutations. The identified genes and cellular functions provide potential targets for development of adjuvants that may block spontaneous resistance evolution when combined with antibiotics.
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Affiliation(s)
- Marta Lukačišinová
- University of Cologne, Institute for Biological Physics, Zülpicher Straße 77, 50937, Cologne, Germany
- IST Austria, Am Campus 1, 3400, Klosterneuburg, Austria
- Department of Biology, Technion - Israel Institute of Technology, Haifa, 32000, Israel
| | - Booshini Fernando
- University of Cologne, Institute for Biological Physics, Zülpicher Straße 77, 50937, Cologne, Germany
| | - Tobias Bollenbach
- University of Cologne, Institute for Biological Physics, Zülpicher Straße 77, 50937, Cologne, Germany.
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Ghosh A, Roymahapatra G, Paul D, Mandal SM. Theoretical analysis of bacterial efflux pumps inhibitors: Strategies in-search of competent molecules and develop next. Comput Biol Chem 2020; 87:107275. [PMID: 32438117 DOI: 10.1016/j.compbiolchem.2020.107275] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 04/01/2020] [Accepted: 04/28/2020] [Indexed: 01/09/2023]
Abstract
Multi-drug resistance (MDR) bacteria pose a significant threat to our ability to effectively treat infections due to the development of several antibiotic resistant mechanisms. A major component in the development of the MDR phenotype in MDR bacteria is over expression of different-type of efflux pumps, which actively pump out antibacterial agents and biocides from the periplasm to the outside of the cell. Consequently, bacterial efflux pumps are an important target for developing novel antibacterial treatments. Potent efflux pump inhibitors (EPIs) could be used as adjunctive therapies that would increase the potency of existing antibiotics and decrease the emergence of MDR bacteria. Several potent inhibitors of efflux pumps have been reported which has been summarized here. All the natural and synthetic EPIs were optimized with Gaussian and Avogadro software. The optimized structures were docked with each class of efflux pumps and their bonding parameters were computed. The theoretical analyses were performed with density functional theory (DFT). Overall, computational study revealed a good trend of electrophilicity and ionization potential of the EPIs, the obtained average values are within in the range of 0.001414 AU ± 0.00032 and 0.208821 AU ± 0.015545, respectively. Interestingly, cathinone interacts with most of the efflux pumps among the tested inhibitors. The electrophilicity and ionization potential of cathinone are 0.00198 and 0.2388 AU, respectively. The study opens a new road for designing future-generation target-specific efflux pump inhibitors, as well as one molecule with multiple inhibition abilities.
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Affiliation(s)
- Akash Ghosh
- Central Research Facility, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | | | - Debarati Paul
- Amity Institute of Biotechnology, Amity University, Sector 125, Noida 201311, India
| | - Santi M Mandal
- Central Research Facility, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
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50
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Kordafshari S, Marenda MS, Agnew R, Shil P, Shahid MA, Marth C, Konsak BM, Noormohammadi AH. Complementation of the Mycoplasma synoviae MS-H vaccine strain with wild-type oppF1 influences its growth characteristics. Avian Pathol 2020; 49:275-285. [PMID: 32054292 DOI: 10.1080/03079457.2020.1729957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The Mycoplasma synoviae (MS) vaccine strain MS-H harbours a frameshift mutation in oppF1 (oligopeptide permease transporter) which results in expression of a truncated OppF1. The effect of this mutation on growth and attenuation of the MS-H is unknown. In this study, the impact of the mutation on the vaccine phenotype was investigated in vitro by introducing a wild-type copy of oppF1 gene in the MS-H genome. Wild-type oppF1 was cloned under the vlhA promoter into an oriC vector carrying a tetracycline resistance gene. MS-H was successfully transformed with the final construct pMS-oppF1-tetM or with a similar vector lacking oppF1 coding sequence (pMS-tetM). The MS-H transformed with pMS-oppF1-tetM exhibited smaller colony size than MS-H transformed with pMS-tetM. Monospecific rabbit sera against C-terminus of OppF1 detected bands of expected size for full-length OppF1 in the 86079/7NS parental strain of MS-H and the MS-H transformed with pMS-oppF1-tetM, but not in MS-H and MS-H transformed with pMS-tetM. Comparison of the growth curve of MS-H transformants harvested from media with/without tetracycline was conducted using vlhA Q-PCR which revealed that MS-H transformed with pMS-tetM had a higher growth rate than MS-H transformed with pMS-oppF1-tetM in the media with/without tetracycline. Lastly, the whole genome sequencing of MS-H transformed with pMS-oppF1-tetM (passage 27) showed that the chromosomal copy of the mutated oppF1 had been replaced with a wild-type version of the gene. This study reveals that the truncation of oppF1 impacts on growth characteristics of the MS-H and provides insight into the molecular pathogenesis of MS and perhaps broader mycoplasma species.RESEARCH HIGHLIGHTS The full-length OppF1 was expressed in Mycoplasma synoviae MS-H vaccine.Truncation of oppF1 impacts on growth characteristics of the MS-H.Chromosomal copy of the mutated oppF1 in MS-H was replaced with wild-type oppF1.
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Affiliation(s)
- Somayeh Kordafshari
- Asia Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Veterinary & Agricultural Sciences, The University of Melbourne, Werribee, Australia
| | - Marc S Marenda
- Asia Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Veterinary & Agricultural Sciences, The University of Melbourne, Werribee, Australia
| | - Rebecca Agnew
- Asia Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Veterinary & Agricultural Sciences, The University of Melbourne, Werribee, Australia
| | - Pollob Shil
- Asia Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Veterinary & Agricultural Sciences, The University of Melbourne, Werribee, Australia
| | - Muhammad A Shahid
- Department of Pathobiology, Faculty of Veterinary Sciences, Bahauddin Zakariya University, Multan, Pakistan
| | - Christina Marth
- Asia Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Veterinary & Agricultural Sciences, The University of Melbourne, Werribee, Australia
| | - Barbara M Konsak
- Asia Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Veterinary & Agricultural Sciences, The University of Melbourne, Werribee, Australia
| | - Amir H Noormohammadi
- Asia Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Veterinary & Agricultural Sciences, The University of Melbourne, Werribee, Australia
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