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. 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.

💡 Research Summary

The paper investigates how slow, non‑zero migration combined with temporal environmental fluctuations can drive the extinction of cooperative antimicrobial resistance (AMR) in a spatially structured microbial metapopulation. The authors model a two‑dimensional lattice of demes, each with a carrying capacity K(t) that alternates between harsh and mild states, thereby creating periodic population bottlenecks. Within each deme, drug‑sensitive (S) and drug‑resistant (R) cells compete for resources. R cells produce a public‑good enzyme (e.g., β‑lactamase) once their local number exceeds a fixed cooperation threshold N_th, protecting both strains from the antimicrobial. This confers a fitness advantage a – s to R when the threshold is met, while S suffers a fitness reduction a due to the drug; otherwise R pays a metabolic cost s.

The intra‑deme dynamics follow a Moran‑type birth‑death process, and cells migrate to the four nearest neighbours at per‑capita rate m (both density‑dependent and density‑independent forms are examined). The authors ask two central questions: (1) at which migration rates can environmental and demographic fluctuations eradicate the resistant strain, and (2) what are the near‑optimal environmental conditions (fluctuation period τ, amplitude of K(t)) that ensure quasi‑certain eradication in the shortest time.

Using analytical extinction‑probability calculations and extensive Gillespie simulations, they find that very low migration leaves demes essentially isolated, so local extinctions of R do not spread, while very high migration homogenises the metapopulation, allowing coexistence as previously reported. In contrast, an intermediate “slow‑but‑nonzero” migration regime (m≈10⁻³–10⁻² per generation) synchronises with the environmental bottlenecks: during harsh phases the population contracts, and the modest migration redistributes cells such that many demes fall below N_th, dramatically increasing the chance that R cannot sustain the public good. When the fluctuation period τ is comparable to the generation time needed for R to reach the threshold, the extinction probability of R across the whole lattice exceeds 0.95 and the mean extinction time is minimised. These results are robust to variations in the shape of K(t) (square or sinusoidal), to one‑dimensional lattices, and to a range of biological parameters (cost s, drug effect a, threshold N_th).

The study proposes experimental validation using microfluidic devices that impose global nutrient or drug flux oscillations while controlling cell motility. The findings overturn the conventional view that migration always promotes AMR spread, showing that carefully tuned slow migration in fluctuating environments can be a powerful strategy to eradicate cooperative resistance. This insight has potential implications for designing treatment regimens and environmental management policies aimed at limiting the persistence of AMR.