Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Front Cell Infect Microbiol. 2022 Aug 22;12:958240. doi: 10.3389/fcimb.2022.958240. eCollection 2022.
Suboptimal efficacy of the current antibiotic regimens and frequent emergence of antibiotic-resistant (Mtb), an etiological agent of tuberculosis (TB), render TB the world's deadliest infectious disease before the COVID-19 outbreak. Our outdated TB treatment method is designed to eradicate actively replicating populations of Mtb. Unfortunately, accumulating evidence suggests that a small population of Mtb can survive antimycobacterial pressure of antibiotics by entering a "persister" state (slowly replicating or non-replicating and lacking a stably heritable antibiotic resistance, termed drug tolerance). The formation of drug-tolerant Mtb persisters is associated with TB treatment failure and is thought to be an adaptive strategy for eventual development of permanent genetic mutation-mediated drug resistance. Thus, the molecular mechanisms behind persister formation and drug tolerance acquisition are a source of new antibiotic targets to eradicate both Mtb persisters and drug-resistant Mtb. As Mtb persisters are genetically identical to antibiotic susceptible populations, metabolomics has emerged as a vital biochemical tool to differentiate these populations by determining phenotypic shifts and metabolic reprogramming. Metabolomics, which provides detailed insights into the molecular basis of drug tolerance and resistance in Mtb, has unique advantages over other techniques by its ability to identify specific metabolic differences between the two genetically identical populations. This review summarizes the recent advances in our understanding of the metabolic adaptations used by Mtb persisters to achieve intrinsic drug tolerance and facilitate the emergence of drug resistance. These findings present metabolomics as a powerful tool to identify previously unexplored antibiotic targets and improved combinations of drug regimens against drug-resistant TB infection.
在 COVID-19 爆发之前，目前抗生素方案的疗效不佳和抗生素耐药性（Mtb）的频繁出现使结核病（TB）成为世界上最致命的传染病。我们过时的结核病治疗方法旨在消灭 Mtb 的活跃复制群体。不幸的是，越来越多的证据表明，一小部分 Mtb 可以通过进入“持久生存者”状态来抵抗抗分枝杆菌药物的压力（缓慢复制或不复制，并且缺乏稳定遗传的抗生素耐药性，称为药物耐受性）。耐药物 Mtb 持久生存者的形成与结核病治疗失败有关，被认为是最终发展为永久性遗传突变介导的耐药性的一种适应策略。因此，持久生存者形成和获得药物耐受性的分子机制是消除 Mtb 持久生存者和耐药 Mtb 的新抗生素靶标的来源。由于 Mtb 持久生存者在遗传上与抗生素敏感群体相同，代谢组学已成为一种重要的生化工具，通过确定表型变化和代谢重编程来区分这些群体。代谢组学通过识别两种遗传上相同的群体之间的特定代谢差异，提供了对 Mtb 药物耐受性和耐药性的分子基础的详细了解，具有比其他技术独特的优势。这篇综述总结了我们对 Mtb 持久生存者用于实现内在药物耐受性和促进耐药性出现的代谢适应的最新理解进展。这些发现表明代谢组学是一种强大的工具，可以识别以前未探索的抗生素靶标，并改善针对耐药性结核病感染的药物方案组合。
