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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 drug-concentration rescaling approach. We show how the resistance to drugs in space, and the consequent adaptation of growth rate, is governed by a Price equation with diffusion, integrating 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. Although in many evolution models, per capita growth rate is a natural surrogate for fitness, in spatially-extended, potentially heterogeneous habitats, fitness is an emergent property that potentially reflects additional complexities, from boundary conditions to the specific spatial variation of growth rates. Applying concepts from perturbation theory and reaction-diffusion equations, we propose an analytical metric for characterization of <jats:italic>average mutant fitness<\/jats:italic> in the spatial system based on the principal eigenvalue of our linear problem, \u03bb<jats:sub>1<\/jats:sub>. This enables an accurate translation from drug spatial gradients and mutant antibiotic susceptibility traits to the relative advantage of each mutant across the environment. Our approach allows one to predict the precise outcomes of selection among mutants over space, ultimately from comparing their \u03bb<jats:sub>1<\/jats:sub> values, which encode a critical interplay between growth functions, movement traits, habitat size and boundary conditions. Such mathematical understanding opens new avenues for multi-drug therapeutic optimization.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012098","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T19:03:36Z","timestamp":1717182216000},"page":"e1012098","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Modeling spatial evolution of multi-drug resistance under drug environmental gradients"],"prefix":"10.1371","volume":"20","author":[{"given":"Tomas Ferreira Amaro","family":"Freire","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijian","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin 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