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.