Bacterial persistence from a system-level perspective

•Persister cells are metabolically active and have a phenotype adapted to stress protection.•Perturbations of metabolic homeostasis might be the common, basic process leading to persister formation.•Feedback mechanisms stabilize the cells in the persister state.•The cellular regulation of resource allocation might be a suitable target to combat persisters.

In recent years, our understanding about bacterial persistence has significantly advanced: we comprehend the persister phenotype better, more triggers for persistence entry have been found, and more insights in the involvement and role of toxin-antitoxin systems and other molecular mechanisms have been unravelled. In this review, we attempt to put these findings into an integrated, system-level perspective. From this point of view, persistence can be seen as a response to a strong perturbation of metabolic homeostasis, either triggered environmentally, or by means of intracellular stochasticity. Metabolic-flux-regulated resource allocation ensures stress protection, and several feedback mechanisms stabilize the cells in this protected state. We hope that this novel view can advance our understanding about persistence.