Active maintenance of proton motive force mediates starvation-induced bacterial antibiotic tolerance in Escherichia coli

Abstract

The proton motive force (PMF) is a critical electrochemical gradient involved in bacterial energy metabolism. Here, Miaomiao Wang, Edward Wai Chi Chan et al. demonstrate that the PMF plays a key role in starvation-induced antibiotic tolerance in E. coli, suggesting that PMF disruption could be a future strategy to treat bacterial infection. Recent evidence suggests that metabolic shutdown alone does not fully explain how bacteria exhibit phenotypic antibiotic tolerance. In an attempt to investigate the range of starvation-induced physiological responses underlying tolerance development, we found that active maintenance of the transmembrane proton motive force (PMF) is essential for prolonged expression of antibiotic tolerance in bacteria. Eradication of tolerant sub-population could be achieved by disruption of PMF using the ionophore CCCP, or through suppression of PMF maintenance mechanisms by simultaneous inhibition of the phage shock protein (Psp) response and electron transport chain (ETC) complex activities. We consider disruption of bacterial PMF a feasible strategy for treatment of chronic and recurrent bacterial infections.