Bacterial Persistence Modulates the Speed, Magnitude, and Onset of Antibiotic Resistance Evolution

Bacterial persistence, a phenomenon where a subpopulation of cells can exhibit increased survival to antibiotic stress, allows part of the population to withstand antibiotic treatment. This can have far-reaching implications for the evolution of antibiotic resistance, yet its evolutionary consequences remain insufficiently understood. Here, using a combination of evolutionary modeling and experimental evolution data on Escherichia coli, we show that persistence impacts the speed, onset, and magnitude of antibiotic resistance evolution. Specifically, high persistence facilitates the slow establishment of small-effect mutations by protecting them from antibiotic killing, while low persistence boosts the rapid yet unpredictable emergence of rare large-effect resistance mutations by amplifying their competitive advantage. Our results show that persistence level has a critical impact on the trade-off between short-term population survival and the evolution of high-level resistance, with distinct outcomes depending on the severity of the antibiotic treatment regimen. These findings provide key insights for designing antibiotic treatment strategies that minimize the risk of antibiotic resistance evolution while maintaining treatment efficacy.