Slow spatial migration can help eradicate cooperative antimicrobial resistance in time-varying environments
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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. Microbial communities generally evolve in volatile, spatially structured settings. Migration, space, fluctuations, and environmental variability all have a significant impact on the development and proliferation of AMR. While drug resistance is enhanced by migration in static conditions, this changes in time-fluctuating spatially structured environments. Here, we consider a two-dimensional metapopulation consisting of demes in which drug-resistant and sensitive cells evolve in a time-changing environment. This contains a toxin against which protection can be shared (cooperative AMR). Cells migrate between demes and connect them. When the environment and the deme composition vary on the same timescale, strong population bottlenecks cause fluctuation-driven extinction events, countered by migration. We investigate the influence of migration and environmental variability on the AMR eco-evolutionary dynamics by asking at what migration rate fluctuations can help clear resistance and what are the near-optimal environmental conditions ensuring the quasi-certain eradication of resistance in the shortest possible time. By combining analytical and computational tools, we answer these questions by determining when the resistant strain goes extinct across the entire metapopulation. While dispersal generally promotes strain coexistence, here we show that slow-but-nonzero migration can speed up and enhance resistance clearance, and determine the near-optimal conditions for this phenomenon. We discuss the impact of our findings on laboratory-controlled experiments and outline their generalisation to lattices of any spatial dimension.
Author summary
As the number of microbes resisting antimicrobial drugs grows alarmingly, it is of paramount importance to tackle this major societal issue. Resistant microbes often inactivate antibiotic drugs 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 temporal 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, homogeneously across all demes. We show that when the environment and the deme composition vary on the same timescale, 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, and outline their generalisation to lattices of any dimension.
