Antibiotic‐tolerant persisters are often implicated in treatment failure of chronic and relapsing bacterial infections, but the underlying molecular mechanisms have remained elusive. Controversies revolve around the relative contribution of specific genetic switches called toxin–antitoxin (TA) modules and global modulation of cellular core functions such as slow growth. Previous studies on uropathogenic Escherichia coli observed impaired persister formation for mutants lacking the pasTI locus that had been proposed to encode a TA module. Here, we show that pasTI is not a TA module and that the supposed toxin PasT is instead the bacterial homolog of mitochondrial protein Coq10 that enables the functionality of the respiratory electron carrier ubiquinone as a “lipid chaperone.” Consistently, pasTI mutants show pleiotropic phenotypes linked to defective electron transport such as decreased membrane potential and increased sensitivity to oxidative stress. We link impaired persister formation of pasTI mutants to a global distortion of cellular stress responses due to defective respiration. Remarkably, the ectopic expression of human coq10 largely complements the respiratory defects and decreased persister levels of pasTI mutants. Our work suggests that PasT/Coq10 has a central role in respiratory electron transport that is conserved from bacteria to humans and sustains bacterial tolerance to antibiotics.

中文翻译：

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作为线粒体Coq10的细菌同源物，大肠杆菌的PasT维持抗生素耐受性和有氧呼吸。

耐抗生素的持久性常与慢性和复发性细菌感染的治疗失败有关，但潜在的分子机制仍然难以捉摸。争议围绕着称为毒素-抗毒素（TA）模块的特定遗传开关的相对贡献以及对细胞核心功能（例如缓慢生长）的整体调节。先前对泌尿致病性大肠杆菌的研究发现，缺少拟定为编码TA模块的pasTI基因座的突变体，其持久性形成受损。在这里，我们展示了pasTI它不是TA模块，而是假定的毒素PasT而是线粒体蛋白Coq10的细菌同源物，它使呼吸电子载体泛醌具有“脂质伴侣”的功能。一致地，pasTI突变体表现出与缺陷的电子传输有关的多效性表型，例如膜电位降低和对氧化应激的敏感性增加。我们将受损的pasTI突变体的持久性形成与由于呼吸不良导致的细胞应激反应的整体畸变联系起来。值得注意的是，人coq10的异位表达在很大程度上弥补了呼吸系统缺陷并降低了pasTI的持久性水平突变体。我们的工作表明，PasT / Coq10在呼吸电子运输中起着核心作用，这种运输从细菌到人类都是保守的，并维持细菌对抗生素的耐受性。