Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations

Abstract

AbstractAntibiotic-resistant pathogens are a major public health threat. Understanding how an antibiotic’s mechanism of action influences the emergence of resistance could help to improve the design of new drugs and to preserve the effectiveness of existing ones. To this end, we developed a model that links bacterial population dynamics with antibiotic-target binding kinetics. Our approach allows us to derive mechanistic insights on drug activity from population-scale experimental data and to quantify the interplay between drug mechanism and resistance selection. We find that whether a drug acts as a bacteriostatic or bactericidal agent has little influence on resistance selection. We also show that heterogeneous drug-target binding within a population enables antibiotic-resistant bacteria to evolve secondary mutations, even when drug doses remain above the resistant strain’s minimum inhibitory concentration. Our work suggests that antibiotic doses beyond this “secondary mutation selection window” could safeguard against the emergence of high-fitness resistant strains during treatment.