Persisters are transiently antibiotic-tolerant cells that complicate the treatment of bacterial infections. Both theory and experiments have suggested that persisters facilitate genetic resistance by constituting an evolutionary reservoir of viable cells. Here, we provide evidence for a strong positive correlation between persistence and the likelihood to become genetically resistant in natural and lab strains of E. coli. This correlation can be partly attributed to the increased availability of viable cells associated with persistence. However, our data additionally show that persistence is pleiotropically linked with mutation rates. Our theoretical model further demonstrates that increased survival and mutation rates jointly affect the likelihood of evolving clinical resistance. Overall, these results suggest that the battle against antibiotic resistance will benefit from incorporating anti-persister therapies.

Persisters are transiently tolerant variants that allow populations to avoid eradication by antibiotic treatment. Their antibiotic tolerance is non-genetic, not inheritable and results from a phenotypic switch from the normal, sensitive cell type to the tolerant, persister state. Here we give a comprehensive overview on bacterial persistence. We first define persistence, summarize the various aspects of persister physiology and show their heterogeneous nature. We then focus on the role of key cellular processes and mechanisms controlling the formation of a subpopulation of tolerant cells. Being a prime example of a risk-spreading strategy, we next discuss the eco-evolutionary aspects of persistence, e.g. how persistence evolves in the face of treatment with antibiotics. Finally, we illustrate the clinical importance of persisters, as persistence is worsening the worldwide antibiotic crisis by prolonging antibiotic treatment, causing therapy failure or catalyzing the development of genetically encoded antibiotic resistance. A better understanding of this phenotype is critical in our fight against pathogenic bacteria and to obtain a better outlook on future therapies.

Certain infectious diseases caused by pathogenic bacteria are typically chronic in nature. Potentially deadly examples include tuberculosis, caused by Mycobacterium tuberculosis, cystic fibrosis-associated lung infections, primarily caused by Pseudomonas aeruginosa, and candidiasis, caused by the fungal pathogen Candida albicans. A hallmark of this type of illness is the recalcitrance to treatment with antibiotics, even in the face of laboratory tests showing the causative agents to be sensitive to drugs. Recent studies have attributed this treatment failure to the presence of a small, transiently multidrug-tolerant subpopulation of cells, so-called persister cells. Here, we review our current understanding of the role that persisters play in the treatment and outcome of chronic infections. In a second part, we offer a perspective on the development of anti-persister therapies based on genes and mechanisms that have been implicated in persistence over the last decade.