Modeling spatial evolution of multi-drug resistance under drug environmental gradients.

Multi-drug combinations to treat bacterial populations are at the forefront of approaches for infection control and prevention of antibiotic resistance. Although the evolution of antibiotic resistance has been theoretically studied with mathematical population dynamics models, extensions to spatial dynamics remain rare in the literature, including in particular spatial evolution of multi-drug resistance. In this study, we propose a reaction-diffusion system that describes the multi-drug evolution of bacteria, based on a rescaling approach (Gjini and Wood, 2021). We show how the resistance to drugs in space, and the consequent adaptation of growth rate is governed by a Price equation with diffusion. The covariance terms in this equation integrate features of drug interactions and collateral resistances or sensitivities to the drugs. We study spatial versions of the model where the distribution of drugs is homogeneous across space, and where the drugs vary environmentally in a piecewise-constant, linear and nonlinear manner. Applying concepts from perturbation theory and reaction-diffusion equations, we propose an analytical characterization of average mutant fitness in the spatial system based on the principal eigenvalue of our linear problem. This enables an accurate translation from drug spatial gradients and mutant antibiotic susceptibility traits, to the relative advantage of each mutant across the environment. Such a mathematical understanding allows to predict the precise outcomes of selection over space, ultimately from the fundamental balance between growth and movement traits, and their diversity in a population.