Environmental heterogeneity facilitates competitive suppression of drug resistance

Abstract

Antimicrobial resistance (AMR) is a growing threat to human health, agriculture, and natural ecosystems. While antimicrobial use is a primary driver of resistance evolution, growing evidence suggests that anthropogenic environmental change may also contribute to the emergence and spread of resistant microbes. Yet the mechanisms linking environmental conditions to AMR remain poorly understood and are largely absent from current strategies to manage resistance. This gap arises, in part, because we still know surprisingly little about how ecological interactions shape the evolutionary dynamics of antimicrobial resistance. Here, we develop a general eco-evolutionary modeling framework to investigate how spatial structure, resource availability, and growth-efficiency trade-offs shape competition between drug-sensitive and drug-resistant strains. We show that spatial heterogeneity influences resistance evolution not simply by strengthening or weakening competition, but by altering the ecological mechanisms through which competition suppresses resistant strains. In homogeneous environments, resistance is suppressed primarily by faster-growing drug-sensitive competitors and only under a relatively narrow range of ecological conditions. In contrast, heterogeneous environments with limited resources favor more resource-efficient drug-sensitive strains, which outcompete resistant strains through a distinct colonization advantage that operates across a broader region of parameter space. These patterns emerge regardless of whether resistant mutants are initially present or arise de novo through mutation. Together, our results provide insight into mechanistic links between environmental change and AMR emergence, suggesting that environmental homogenization and resource enrichment may reduce opportunities for competitive suppression and thereby increase resistance risk. More broadly, this work demonstrates how ecological interactions and environmental structure shape the evolution of resistance and offers possible insight into resistance management. Author summaryAntimicrobial resistance (AMR) is often viewed as a direct consequence of antimicrobial use. However, mounting evidence suggests that ecological processes may often suppress resistant strains before they can emerge and spread. Despite growing recognition that ecological interactions influence AMR, we still know relatively little about the environmental conditions that strengthen or weaken those interactions. We developed a general eco-evolutionary modeling framework that integrates consumer-resource theory, spatial ecology, and stochastic trait evolution to investigate how spatial structure, resource availability, and growth-efficiency trade-offs shape competition between drug-sensitive and drug-resistant strains. Whereas previous theoretical and empirical work has largely focused on spatial variation in antimicrobial exposure, our framework examines how spatial variation in resource availability interacts with growth-efficiency trade-offs to influence the evolutionary dynamics of AMR. Our analyses reveal that environmental heterogeneity does not simply strengthen or weaken competition; it fundamentally alters the ecological mechanisms through which competition suppresses resistance. In homogeneous environments, resistance is constrained primarily by faster-growing sensitive strains but only under a relatively narrow range of ecological conditions. In contrast, heterogeneous environments favor more resource-efficient competitors that suppress resistant strains through a distinct colonization-based mechanism that operates across a larger region of parameter space. The key takeaway is not just that spatial structure or resource availability matter for AMR. Instead, the main lesson is that environmental homogenization may help promote AMR. Because many human activities homogenize environments (e.g., invasive plants, chemically intensive agriculture typical across much of the US Corn Belt), it is critical to determine whether they do so at the spatial scales relevant to microbial competition. Future studies integrating AMR surveillance data and environmental metadata with this eco-evolutionary model could help move environmental heterogeneity and microbial community structure from correlates of resistance into mechanistic predictors of AMR.