The effect of spatiotemporal antibiotic inhomogeneities on the evolution of resistance

Combating the evolution of widespread antibiotic resistance is one of the most pressing challenges facing modern medicine. Recent research has demonstrated that the evolution of pathogens with high levels of resistance can be accelerated by spatial and temporal inhomogeneities in antibiotic concentration, which frequently arise in patients and the environment. Strategies to predict and counteract the effects of such inhomogeneities will be critical in the fight against resistance. In this paper we develop a mechanistic framework for modelling the adaptive evolution of resistance in the presence of spatiotemporal antibiotic concentrations, which treats the adaptive process as an interaction between two mutually orthogonal forces; the first returns cells to their wild-type state in the absence of antibiotic selection, and the second selects for increased coping ability in the presence of an antibiotic. We apply our model to investigate laboratory adaptation experiments, and then extend it to consider the case in which multiple strategies for resistance undergo competitive evolution.