Phenotypic Heterogeneity Facilitates Survival While Hindering the Evolution of Drug Resistance

Rising rates of resistance to antimicrobial drugs threatens the effective treatment of infections across the globe. Recently, it has been shown that drug resistance can emerge from non-genetic mechanisms, such as fluctuations in gene expression, as well as from genetic mutations. However, it is unclear how non-genetic drug resistance affects the evolution of genetic drug resistance. We develop deterministic and stochastic population models to quantitatively investigate the transition from non-genetic to genetic resistance during the exposure to static and cidal drugs. We find that non-genetic resistance facilitates the survival of cell populations during drug treatment, but that it hinders the development of genetic resistance due to competition between the non-genetically and genetically resistant subpopulations. The presence of non-genetic drug resistance is found to increase the first-appearance, establishment, and fixation times of drug resistance mutations, while increasing the probability of mutation before population extinction during cidal drug treatment. These findings advance our fundamental understanding of the evolution of drug resistance and may guide novel treatment strategies for patients with drug-resistant infections. SIGNIFICANCE Antimicrobial (drug) resistance is predicted to kill as many as 10 million people per year and cost over 100 trillion USD in cumulative lost production globally by 2050. To mitigate these socio-economic costs, we need to fundamentally understand the drug resistance process. We investigate the effect that different forms of drug resistance have on the evolution of drug resistance using mathematical modeling and computer simulations. We find that the presence of non-genetically drug-resistant cells (whose resistance is temporary and not encoded in a genetic mutation) allows the population to survive drug treatment, while at the same time slowing down the evolution of permanent genetic drug resistance. These findings have important implications for advancing evolutionary theory and for developing effective “resistance-proof” treatments.