Mycobacterial persistence mechanisms remain to be fully characterized. Screening a transposon insertion library of Mycobacterium marinum identified kdpA, whose inactivation reduced the fraction of persisters after exposure to rifampicin. kdpA encodes a transmembrane protein that is part of the Kdp-ATPase, an ATP-dependent high-affinity potassium (K+) transport system. We found that kdpA is induced under low K+ conditions and is required for pH homeostasis and growth in media with low concentrations of K+. The inactivation of the Kdp system in a kdpA insertion mutant caused hyperpolarization of the cross-membrane potential, increased proton motive force (PMF) and elevated levels of intracellular ATP. The KdpA mutant phenotype could be complemented with a functional kdpA gene or supplementation with high K+ concentrations. Taken together, our results suggest that the Kdp system is required for ATP homeostasis and persister formation. The results also confirm that ATP-mediated regulation of persister formation is a general mechanism in bacteria, and suggest that K+ transporters could play a role in the regulation of ATP levels and persistence. These findings could have implications for the development of new drugs that could either target persisters or reduce their presence.

中文翻译：

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钾转运蛋白KdpA通过调节海洋分枝杆菌中的ATP水平来影响持久性形成。

分枝杆菌的持久性机制仍有待充分表征。筛选海洋分枝杆菌的转座子插入文库鉴定出kdpA，其失活减少了暴露于利福平后的持久性分数。kdpA编码跨膜蛋白，该蛋白是Kdp-ATPase（ATP依赖性高亲和力钾（K +）转运系统）的一部分。我们发现kdpA在低K +条件下被诱导，并且是pH稳态和在低K +浓度的培养基中生长所必需的。KdpA插入突变体中Kdp系统的失活导致跨膜电位超极化，质子动力（PMF）增加和细胞内ATP水平升高。KdpA突变表型可以与功能性kdpA基因互补或补充高K +浓度。在一起 我们的结果表明，Kdp系统是ATP稳态和持久性形成所必需的。结果还证实，ATP介导的持久性蛋白形成的调控是细菌的一般机制，并表明K +转运蛋白可能在ATP水平和持久性的调控中发挥作用。这些发现可能会对开发新药产生影响，这些新药可能针对持久性药物或减少其存在。