Environmental heterogeneity facilitates competitive suppression of drug resistance
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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.
Author summary
Managing antimicrobial resistance will require strategies that extend beyond reliance on new or existing antimicrobials. An emerging paradigm is that harnessing ecological interactions may enable us to constrain or event prevent the emergence of drug resistance, rather than continually chasing it. We show that rather than relying on directly killing resistant bacteria, resistance can be limited by via competitive interactions between drug-sensitive and drug-resistant strains, but the best strategy depends on environmental conditions. Environmental homogenization and nutrient enrichment can promote the persistence and evolution of antimicrobial resistance because they limit opportunities for competitive suppression. In contrast, environmental heterogeneity favors drug-sensitive strains that use resources more efficiently. Under these conditions, resistant strains are suppressed before they can spread or evolve. These results may help explain why drug-resistant pathogens persist in some patients of environmental hot spots. Additionally, these results help mechanistically explain why promoting more diverse and heterogeneous microbiomes through, for example, probiotics or regenerative agricultural practices, can provide a powerful strategy to manage antimicrobial resistance.
