Abstract
Antimicrobial resistance (AMR) is a growing global threat that, in the absence of new antibiotics, requires effective management of existing drugs. Here, we use experimental evolution of the opportunistic human pathogen Pseudomonas aeruginosa to explore how changing patterns of drug delivery modulates the spread of resistance in a population. Resistance evolves readily under both temporal and spatial variation in drug delivery and fixes rapidly under temporal, but not spatial, variation. Resistant and sensitive genotypes coexist in spatially varying conditions due to a resistance‐growth rate trade‐off which, when coupled to dispersal, generates negative frequency‐dependent selection and a quasi‐protected polymorphism. Coexistence is ultimately lost, however, because resistant types with improved growth rates in the absence of drug spread through the population. These results suggest that spatially variable drug prescriptions can delay but not prevent the spread of resistance and provide a striking example of how the emergence and eventual demise of biodiversity is underpinned by evolving fitness trade‐offs.
Highlights
The effectiveness of antibiotic therapy to control infection is being steadily undermined by the combination of divestment in drug discovery, widespread occurrence of genetic resistance among microbes isolated from natural environments (Nesme et al, 2014), and continued evolution of resistant strains among all major pathogens (Hidron et al, 2008)
These results suggest that divergent selection leads to the stable coexistence of resistant and sensitive strains through negative frequency dependent selection, consistent with predictions from models for the maintenance of polymorphism in spatially variable environments (Levene, 1953; Dempster, 1955; Kisdi, 2001)
The manner in which drug sanctuaries are experienced by a pathogen can impact the rate at which resistance spreads in a population: while temporal variation in drug sanctuaries does little to prevent the rise of resistance, spatially distributed sanctuaries can slow the rate at which resistance fixes in a population
Summary
The steady rise of antimicrobial resistance (AMR) in most human pathogens is a critical health threat that requires multidisciplinary attention, including from the fields of evolutionary biology and ecology. There is strong evidence that resistant strains often pay a cost of resistance in terms of reduced growth rate and fitness in the absence of antibiotic (Ender et al, 2004; Hurdle et al, 2004; Wong et al, 2012; Melnyk et al, 2015), generating fitness trade-offs like those required in models for the maintenance of diversity in spatially heterogeneous environments (Levene, 1953; Dempster, 1955; Kisdi, 2001). A sensitive genotype very obviously has low fitness in the presence of the drug (the cell is either killed or prevented from growing) but has much higher fitness in drug free conditions, meaning we can consider it a specialist in the absence of drugs Should both types be present in a population, the first condition for the maintenance of diversity under spatially variable selection – a trade-off in fitness across environments – in the Levene (1953) model is satisfied. These results suggest that spatially variable drug prescriptions can delay but not prevent the spread of resistance and provide a striking example of how the emergence and eventual demise of biodiversity is underpinned by evolving fitness trade-offs
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