Proton motive force and antibiotic tolerance in bacteria

Bacterial antibiotic tolerance is a decades-old phenomenon in which a bacterial sub-population, commonly known as persisters, does not respond to antibiotics and remains viable upon prolonged antimicrobial treatment. Persisters are detectable in populations of bacterial strains that are not antibiotic-resistant and are known to be responsible for treatment failure and the occurrence of chronic and recurrent infection. The clinical significance of antibiotic tolerance is increasingly being recognized and comparable to antibiotic resistance. To eradicate persisters, it is necessary to understand the cellular mechanisms underlying tolerance development. Previous works showed that bacterial antibiotic tolerance was attributed to the reduction in metabolic activities and activation of the stringent response, SOS response and the toxin-antitoxin system which down-regulates transcription functions. The latest research findings, however, showed that decreased metabolic activities alone do not confer a long-lasting tolerance phenotype in persisters, and that active defence mechanisms such as efflux and DNA repair are required for the long-term maintenance of phenotypic tolerance. As such active tolerance-maintenance mechanisms are energy-demanding, persisters need to generate and maintain the transmembrane proton motive force (PMF) for oxidative phosphorylation. This minireview summarizes the current understanding of cellular mechanisms essential for prolonged expression of phenotypic antibiotic tolerance in bacteria, with an emphasis on the importance of generation and maintenance of PMF in enabling proper functioning of the active tolerance mechanisms in persisters. How such mechanisms can be utilized as targets for the development of anti-persister strategies will be discussed.