Ecological determinants and evolutionary landscapes of antibiotic resistance
Embargo Date
2027-02-10
OA Version
Citation
Abstract
Antibiotics are a critical element of modern health care that is threatened by the microbes’ natural propensity to evolve resistance. Experimental evolution of antimicrobial resistance (AMR) is a powerful in vitro approach that enables precise control over culture conditions and direct observation of mutational trajectories to resistance. However, experimental evolution studies have largely overlooked the ecological context of AMR evolution in the natural world; many of the environments in which microbes are naturally selected by antibiotics are oxygen-limited. Notably, the microbially diverse human gut is largely anaerobic and can serve as a reservoir for antibiotic-resistant pathogens. To systematically address this gap in understanding of how oxygen impacts the de novo evolution of AMR, we experimentally evolved clinical isolate strains of E. coli towards resistance in either aerobic or anaerobic conditions. Cultures were serially passaged across dynamically tuned antibiotic gradients, which tracked the emerging resistance of independent lineages over time. Evolved populations were then whole-genome resequenced to resolve mutational landscapes across selective conditions. We discover that evolution in oxygen-rich environments is strongly associated with higher heritable resistance and mutation count for ciprofloxacin and cefoxitin, moderately for tetracycline, but not for gentamicin. Across antibiotics, a strain’s capacity to accumulate fixed mutations correlates tightly with their respective acquired resistances. Furthermore, high-frequency, resistance-associated mutations in core genes are preferentially selected in specific atmospheric contexts. For gentamicin resistance, components of central bioenergetic machinery – cytochrome bd oxidase and ATP synthase – are specifically mutated in aerobic and anaerobic conditions, respectively. This suggests that the microbial environment can constrain and modulate evolutionary trajectories to resistance due to its effects on the fitness landscapes of key antibiotic resistance genes. By unraveling the eco-evolutionary principles that underly antimicrobial resistance, we stand to discover novel strategies and targets to ultimately control the lethal emergence of antimicrobial resistance.
Description
2026