Slow spatial migration can help eradicate cooperative antimicrobial resistance in time-varying environments

Antimicrobial resistance (AMR) is a global threat and combating its spread is of paramount importance. AMR often results from a cooperative behaviour with shared drug protection. Micro-bial communities generally evolve in volatile, spatially structured settings. Migration, fluctuations, and environmental variability significantly impact AMR. While AMR is enhanced by migration in static conditions, this changes in time-fluctuating spatially structured environments. We consider a two-dimensional metapopulation consisting of demes in which drug-resistant and sensitive cells evolve in a time-changing environment containing a toxin against which protection can be shared. Cells migrate between demes and connect them. When the environment varies neither too quickly nor too slowly, population bottlenecks cause fluctuation-driven extinctions, countered by migration. We investigate the influence of migration and environmental variability on AMR, determining the near-optimal conditions for resistance eradication. We show how slow migration speeds up and enhances AMR clearance. We discuss our studys impact on laboratory-controlled experiments. Author summaryAs the number of microbes resisting antimicrobial drugs grows alarmingly, it is of paramount importance to tackle this major societal issue. Resistant microbes often inhibit antibiotics in the environment around them, and hence offer protection to drug-sensitive bacteria in a form of cooperative behaviour. Moreover, microbes typically are distributed in space and live in time-changing environments, where they are subject to random fluctuations. Environmental variability, fluctuations, and spatial dispersal all have a strong influence on the drug resistance of microbial organisms. Here we investigate the evolution of antimicrobial resistance in time-varying spatial environments by combining computational and mathematical means. We study the dynamics of drug-resistant and sensitive cells in the presence of an antimicrobial drug, when microbes are spatially distributed across a two-dimensional grid of well-mixed sub-populations (demes). Cells migrate between neighbouring demes, connecting these sub-populations, and are subject to sudden changes of environment. We show that when environmental variations occur neither too rarely nor too often, the joint effect of slow migration and fluctuations can help eradicate drug resistance by speeding up and enhancing the extinction probability of resistant bacteria. We also discuss how our findings can be probed in laboratory experiments.