“Viable but nonculturable” states of bacteria pose challenges for environmental and clinical microbiology, but their biological mechanisms remain obscure. Mycobacterium tuberculosis (Mtb), the leading cause of death from infection until the coronavirus disease 2019 pandemic, affords a notable example of this phenotype. Mtb can enter into a “differentially detectable” (DD) state associated with phenotypic antimicrobial resistance. In this state, Mtb cells are viable but undetectable as colony-forming units. We found that Mtb cells enter the DD state when they undergo sublethal oxidative stress that damages their DNA, proteins, and lipids. In addition, their replication process is delayed, allowing time for repair. Mycobacterium bovis and its derivative, BCG, fail to enter the DD state under similar conditions. These findings have implications for tuberculosis latency, detection, relapse, treatment monitoring, and development of regimens that overcome phenotypic antimicrobial resistance.

中文翻译：

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氧化损伤和延迟复制使活的结核分枝杆菌无法被发现

“可存活但不可培养”的细菌状态对环境和临床微生物学提出了挑战，但它们的生物学机制仍然不清楚。结核分枝杆菌(Mtb) 是 2019 年冠状病毒病大流行之前因感染而死亡的主要原因，它提供了这种表型的一个显着例子。Mtb 可以进入与表型抗菌素耐药性相关的“差异可检测”（DD）状态。在这种状态下，Mtb 细胞是有活力的，但作为集落形成单位无法检测到。我们发现 Mtb 细胞在受到亚致死氧化应激损害其 DNA、蛋白质和脂质时进入 DD 状态。此外，它们的复制过程被延迟，从而有时间进行修复。牛分枝杆菌及其衍生物BCG在类似条件下无法进入DD状态。这些发现对结核病潜伏期、检测、复发、治疗监测以及克服表型抗菌素耐药性的方案开发具有重要意义。