Environmental heterogeneity facilitates competitive suppression of drug resistance

Antimicrobial resistance is an emergent property of ecological interactions within complex microbial communities. Environmental perturbations, such as high-dose antimicrobial treatment, can alter competitive interactions in ways that either promote or suppress drug-resistant pathogens. Leveraging these competitive interactions shows promise in managing drug resistance in cancer, malaria, and bacteria. However, the broader utility of this approach remains limited by an incomplete understanding of how selective pressures imposed by antimicrobials interact with other environmental factors to shape the emergence and persistence of resistance. Here, we develop a general mathematical framework for investigating how environmental context, including homogenization, resource availability, and growth-efficiency trade-offs that are relevant for bacterial competition shape resistance dynamics. Anthropogenic changes can modify each of these factors in systems such as the gut and soil microbiomes, which are increasingly recognized as critical reservoirs of antimicrobial-resistant bacteria. Our results suggest that environmental structure determines not only whether resistance can be suppressed, but which competitive mechanisms can do so. Environmental homogenization creates a narrow set of conditions under which faster-growing drug-sensitive strains can suppress resistant competitors. In contrast, environmental heterogeneity combined with resource limitation can enable efficient drug-sensitive strains to competitively suppress drug-resistant strains and prevent the evolution of drug resistance. Together, these results join mounting evidence that ecological interactions can be leveraged alongside traditional interventions to more effectively limit antimicrobial resistance. More broadly, our results indicate that anthropogenic pressures that homogenize environments and eliminate competitors may increase the risk of promoting the evolution of drug resistance.