Membrane depolarization-triggered responsive diversification leads to antibiotic tolerance

Abstract

Bacterial populations are known to harbor a small fraction of so-called persister cells that have the remarkable ability to survive treatment with very high doses of antibiotics. Recent studies underscore the importance of persistence in chronic infections, yet the nature of persisters remains poorly understood. We recently showed that the universally conserved GTPase Obg modulates persistence via a (p)ppGpp-dependent mechanism that proceeds through expression of hokB. HokB is a membrane-bound toxin that causes the membrane potential to collapse. The resulting drop in cellular energy levels triggers a switch to the persistent state, yielding protection from antibiotic attack. Obg-mediated persistence is conserved in the human pathogen Pseudomonas aeruginosa, making Obg a promising target for therapies directed against bacterial persistence.

Keywords: (p)ppGpp; CgtA; HokB; Obg; ObgE; YhbZ; antibiotic tolerance; membrane depolarization; persistence; responsive diversification; toxin antitoxin.

Figure 1. FIGURE 1: A model for Obg-mediated persistence.

Stochastic fluctuations in Obg concentrations drive expression of HokB in a (p)ppGpp-dependent manner. HokB protects the cells from antibiotic attack by reducing the membrane potential. Persister cells surviving antibiotic treatment give rise to a new population. See text for details.