Phenotypic Heterogeneity Facilitates Survival While Hindering the Evolution of Drug Resistance Due to Intraspecific Competition

Rising rates of resistance to antimicrobial drugs threatens the effective treatment of infections across the globe. Drug resistance has been established to emerge from non-genetic mechanisms, such as "persistence" in quiescent microbes and fluctuations in gene expression in actively replicating cells, as well as from genetic mutations. However, it is still unclear how non-genetic drug resistance affects the evolution of genetic drug resistance. We develop deterministic and stochastic population models that incorporate resource competition 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 the competition between the non-genetically and genetically resistant subpopulations. Non-genetic drug resistance in the presence of subpopulation competition is found to increase the first-appearance and fixation times of drug resistance mutations, while increasing the probability of mutation before population extinction during cidal drug treatment. Intense intraspecific competition during drug treatment leads to extinction of the susceptible and non-genetically resistant subpopulations. These findings advance our fundamental understanding of the evolution of drug resistance and may guide novel treatment strategies for patients with drug-resistant infections. SIGNIFICANCEDrug 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 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 competition between these subpopoulations simultaneously slows down the evolution of permanent genetic drug resistance and in some cases drives them extinct. These findings have important implications for advancing evolutionary theory and for developing effective "resistance-proof" treatments.