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.

Antibiotic resistance poses an alarming and ever-increasing threat to modern health care. Although the current antibiotic crisis is widely acknowledged, actions taken so far have proved insufficient to slow down the rampant spread of resistant pathogens. Problematically, routine screening methods and strategies to restrict therapy failure almost exclusively focus on genetic resistance, while evidence for dangers posed by other bacterial survival strategies is mounting.

Bacteria are well known for their extremely high adaptability in stressful environments. The clinical relevance of this property is clearly illustrated by the ever-decreasing efficacy of antibiotic therapies. Frequent exposures to antibiotics favor bacterial strains that have acquired mechanisms to overcome drug inhibition and lethality. Many strains, including life-threatening pathogens, exhibit increased antibiotic resistance or tolerance, which considerably complicates clinical practice. Alarmingly, recent studies show that in addition to resistance, tolerance levels of bacterial populations are extremely flexible in an evolutionary context. Here, we summarize laboratory studies providing insight in the evolution of resistance and tolerance and shed light on how the treatment conditions could affect the direction of bacterial evolution under antibiotic stress.