Toxin-antitoxin (TA) systems are widespread in bacteria and implicated in genome stability, virulence, phage defense, and persistence. TA systems have diverse activities and cellular targets, but their physiological roles and regulatory mechanisms are often unclear. Here, we show that the NatR-NatT TA system, which is part of the core genome of the human pathogen Pseudomonas aeruginosa, generates drug-tolerant persisters by specifically depleting nicotinamide dinucleotides. While actively growing P. aeruginosa cells compensate for NatT-mediated NAD+ deficiency by inducing the NAD+ salvage pathway, NAD depletion generates drug-tolerant persisters under nutrient-limited conditions. Our structural and biochemical analyses propose a model for NatT toxin activation and autoregulation and indicate that NatT activity is subject to powerful metabolic feedback control by the NAD+ precursor nicotinamide. Based on the identification of natT gain-of-function alleles in patient isolates and on the observation that NatT increases P. aeruginosa virulence, we postulate that NatT modulates pathogen fitness during infections. These findings pave the way for detailed investigations into how a toxin-antitoxin system can promote pathogen persistence by disrupting essential metabolic pathways.

中文翻译：

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毒素介导的 NAD 和 NADP 耗竭会推动人类病原体中持续存在的形成。


毒素-抗毒素 （TA） 系统广泛存在于细菌中，与基因组稳定性、毒力、噬菌体防御和持久性有关。TA 系统具有不同的活动和细胞靶标，但它们的生理作用和调节机制通常不清楚。在这里，我们表明 NatR-NatT TA 系统是人类病原体铜绿假单胞菌核心基因组的一部分，通过特异性消耗烟酰胺二核苷酸来产生耐药持久性。虽然活跃生长的铜绿假单胞菌细胞通过诱导 NAD + 挽救途径来补偿 NatT 介导的 NAD + 缺陷，但 NAD 耗竭在营养有限的条件下会产生耐药的持续存在者。我们的结构和生化分析提出了一种 NatT 毒素激活和自动调节的模型，并表明 NatT 活性受到 NAD + 前体烟酰胺的强大代谢反馈控制。基于在患者分离株中鉴定 natT 功能获得性等位基因以及观察到 NatT 增加铜绿假单胞菌毒力，我们假设 NatT 在感染期间调节病原体适应性。这些发现为详细研究毒素-抗毒素系统如何通过破坏基本代谢途径来促进病原体持久性铺平了道路。