William J Jowsey, Gregory M Cook, Matthew B McNeil
{"title":"Antibiotic resistance in <i>Mycobacterium tuberculosis</i> alters tolerance to cell wall-targeting inhibitors.","authors":"William J Jowsey, Gregory M Cook, Matthew B McNeil","doi":"10.1093/jacamr/dlae086","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>A limited ability to eliminate drug-resistant strains of <i>Mycobacterium tuberculosis</i> is a major contributor to the morbidity of TB. Complicating this problem, little is known about how drug resistance-conferring mutations alter the ability of <i>M. tuberculosis</i> to tolerate antibiotic killing. Here, we investigated if drug-resistant strains of <i>M. tuberculosis</i> have an altered ability to tolerate killing by cell wall-targeting inhibitors.</p><p><strong>Methods: </strong>Bacterial killing and MIC assays were used to test for antibiotic tolerance and synergy against a panel of drug-resistant <i>M. tuberculosis</i> strains.</p><p><strong>Results: </strong>Our results demonstrate that vancomycin and thioacetazone exhibit increased killing of diverse drug-resistant strains. Mutations in <i>mmaA4</i> and <i>mmpL3</i> increased vancomycin killing, which was consistent with vancomycin synergizing with thioacetazone and MmpL3-targeting inhibitors. In contrast, mutations in the <i>mce1</i> operon conferred tolerance to vancomycin.</p><p><strong>Conclusions: </strong>Overall, this work demonstrates how drug-resistant strains experience perturbations in cell-wall production that alters their tolerance to killing by cell wall-targeting inhibitors.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148391/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAC-Antimicrobial Resistance","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/jacamr/dlae086","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
引用次数: 0
Abstract
Background: A limited ability to eliminate drug-resistant strains of Mycobacterium tuberculosis is a major contributor to the morbidity of TB. Complicating this problem, little is known about how drug resistance-conferring mutations alter the ability of M. tuberculosis to tolerate antibiotic killing. Here, we investigated if drug-resistant strains of M. tuberculosis have an altered ability to tolerate killing by cell wall-targeting inhibitors.
Methods: Bacterial killing and MIC assays were used to test for antibiotic tolerance and synergy against a panel of drug-resistant M. tuberculosis strains.
Results: Our results demonstrate that vancomycin and thioacetazone exhibit increased killing of diverse drug-resistant strains. Mutations in mmaA4 and mmpL3 increased vancomycin killing, which was consistent with vancomycin synergizing with thioacetazone and MmpL3-targeting inhibitors. In contrast, mutations in the mce1 operon conferred tolerance to vancomycin.
Conclusions: Overall, this work demonstrates how drug-resistant strains experience perturbations in cell-wall production that alters their tolerance to killing by cell wall-targeting inhibitors.