Phenotypic Heterogeneity Facilitates Survival While Hindering the Evolution of Drug Resistance

Drug resistance has recently been shown to emerge from non-genetic mechanisms, such as "persistence" in quiescent microbes and fluctuations in gene expression in actively replicating cells, as well as genetic mutations. However, it is still unclear if 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.