Diffusion-driven enhancement of the antibiotic resistance selection window

Abstract

The current crisis of antimicrobial resistance in clinically relevant pathogens has highlighted our limited understanding of the ecological and evolutionary forces that drive drug resistance adaptation. For instance, although human tissues are highly heterogeneous, most of our mechanistic understanding about antibiotic resistance evolution is based on constant and well-mixed environmental conditions. A consequence of considering spatial heterogeneity is that, even if antibiotics are prescribed at high dosages, the penetration of drug molecules through tissues inevitably produces antibiotic gradients, exposing bacterial populations to a range of selective pressures and generating a dynamic fitness landscape that changes in space and time. In this paper, we will use a combination of mathematical modelling and computer simulations to study the population dynamics of susceptible and resistant strains competing for resources in a network of micro-environments with varying degrees of connectivity. Our main result is that highly connected environments increase diffusion of drug molecules, enabling resistant phenotypes to colonize a larger number of spatial locations. We validated this theoretical result by culturing fluorescently labelled Escherichia coli in 3D-printed devices that allow us to control the rate of diffusion of antibiotics between neighbouring compartments and quantify the spatio-temporal distribution of resistant and susceptible bacterial cells.