William J Jowsey, Gregory M Cook, Matthew B McNeil
{"title":"结核分枝杆菌的抗生素耐药性改变了对细胞壁靶向抑制剂的耐受性。","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":"{\"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}","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
摘要
背景:消除结核分枝杆菌耐药菌株的能力有限,是导致结核病发病率的主要原因。使这一问题更加复杂的是,人们对耐药性突变如何改变结核分枝杆菌耐受抗生素杀灭的能力知之甚少。在此,我们研究了耐药菌株是否改变了耐受细胞壁靶向抑制剂杀灭的能力:方法:使用杀菌和 MIC 试验来检测抗生素对耐药结核杆菌株的耐受性和协同作用:结果:我们的研究结果表明,万古霉素和硫代乙酰唑酮对多种耐药菌株的杀灭作用增强。mmaA4 和 mmpL3 的突变增加了万古霉素的杀伤力,这与万古霉素与硫代乙酰唑酮和 MmpL3 靶向抑制剂的协同作用是一致的。与此相反,mce1操作子的突变则赋予了万古霉素耐受性:总之,这项工作证明了耐药菌株如何经历细胞壁生产的扰动,从而改变它们对细胞壁靶向抑制剂的耐受性。
Antibiotic resistance in Mycobacterium tuberculosis alters tolerance to cell wall-targeting inhibitors.
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.