Physiologic and environmental factors can modulate antibiotic activity and thus pose a significant challenge to antibiotic treatment. The quinolone class of antibiotics, which targets bacterial topoisomerases, fails to kill bacteria that have grown to high density; however, the mechanistic basis for this persistence is unclear. Here, we show that exhaustion of the metabolic inputs that couple carbon catabolism to oxidative phosphorylation is a primary cause of growth phase-dependent persistence to quinolone antibiotics. Supplementation of stationary-phase cultures with glucose and a suitable terminal electron acceptor to stimulate respiratory metabolism is sufficient to sensitize cells to quinolone killing. Using this approach, we successfully sensitize high-density populations of Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis to quinolone antibiotics. Our findings link growth-dependent quinolone persistence to discrete impairments in respiratory metabolism and identify a strategy to kill non-dividing bacteria.

生理和环境因素可以调节抗生素活性，因此对抗生素治疗提出了重大挑战。针对细菌拓扑异构酶的喹诺酮类抗生素无法杀死已生长到高密度的细菌。但是，这种持久性的机制基础尚不清楚。在这里，我们表明，将碳分解代谢耦合到氧化磷酸化的代谢输入的耗尽是对喹诺酮类抗生素生长相依存的持久性的主要原因。补充葡萄糖和合适的末端电子受体以刺激呼吸代谢的固定相培养足以使细胞对喹诺酮杀死敏感。使用这种方法，我们成功地使高密度大肠杆菌群体敏感，金黄色葡萄球菌和耻垢分枝杆菌对喹诺酮类抗生素。我们的发现将依赖生长的喹诺酮持久性与呼吸代谢的离散损伤联系起来，并确定了杀死非分裂细菌的策略。