Bactericidal antibiotics are powerful agents due to their ability to convert essential bacterial functions into lethal processes. However, many important bacterial pathogens are remarkably tolerant against bactericidal antibiotics due to inducible damage repair responses. The cell wall damage response two‐component system VxrAB of the gastrointestinal pathogen Vibrio cholerae promotes high‐level β‐lactam tolerance and controls a gene network encoding highly diverse functions, including negative control over multiple iron uptake systems. How this system contributes to tolerance is poorly understood. Here, we show that β‐lactam antibiotics cause an increase in intracellular free iron levels and collateral oxidative damage, which is exacerbated in the ∆vxrAB mutant. Mutating major iron uptake systems dramatically increases ∆vxrAB tolerance to β‐lactams. We propose that VxrAB reduces antibiotic‐induced toxic iron and concomitant metabolic perturbations by downregulating iron uptake transporters and show that iron sequestration enhances tolerance against β‐lactam therapy in a mouse model of cholera infection. Our results suggest that a microorganism's ability to counteract diverse antibiotic‐induced stresses promotes high‐level antibiotic tolerance and highlights the complex secondary responses elicited by antibiotics.

中文翻译：

---

多方面的细胞损伤修复和预防途径促进对β-内酰胺类抗生素的高度耐受

杀菌抗生素是强大的药剂，因为它们能够将基本的细菌功能转化为致命的过程。然而，由于可诱导的损伤修复反应，许多重要的细菌病原体对杀菌抗生素具有显着的耐受性。胃肠道病原体霍乱弧菌的细胞壁损伤反应双组分系统 VxrAB促进高水平的 β-内酰胺耐受性并控制编码高度多样化功能的基因网络，包括对多个铁摄取系统的负控制。这个系统如何促进耐受性尚不清楚。在这里，我们表明 β-内酰胺类抗生素会导致细胞内游离铁水平的增加和附带的氧化损伤，这在 Δ vxrAB中更加严重。突变体。主要的铁摄取系统发生突变会显着增加ΔvxrAB对 β-内酰胺的耐受性。我们建议 VxrAB 通过下调铁摄取转运蛋白来减少抗生素诱导的有毒铁和伴随的代谢扰动，并表明铁螯合增强了霍乱感染小鼠模型对 β-内酰胺治疗的耐受性。我们的研究结果表明，微生物抵抗各种抗生素引起的压力的能力促进了高水平的抗生素耐受性，并突出了抗生素引发的复杂的继发性反应。