LAUSR

Antibiotic resistance encoded on plasmids is a pressing global health problem. Predicting which plasmids spread/decline in the long term remains a huge challenge, even though some key parameters influencing plasmid stability have been identified, such as plasmid growth costs and horizontal transfer rates. Here, we show these parameters evolve in a strain-specific way among clinical plasmids/bacteria, and this occurs rapidly enough to alter the relative likelihoods of different bacterium-plasmid combinations spreading/declining. We used experiments with Escherichia coli and antibiotic-resistance plasmids isolated from patients, paired with a mathematical model, to show long-term plasmid stability (beyond antibiotic exposure) was better explained by evolutionary changes in plasmid-stability traits than by initial variation among bacterium-plasmid combinations. Evolutionary trajectories were specific to particular bacterium-plasmid combinations. Genome sequencing and genetic manipulation helped explain this, revealing epistatic (here, strain-dependent) effects of key genetic changes affecting horizontal plasmid transfer. Several genetic changes involved mobile elements and pathogenicity islands. Rapid strain-specific evolution can thus outweigh ancestral phenotypes as a predictor of plasmid stability. Accounting for strain-specific plasmid evolution in natural populations could improve our ability to anticipate and manage successful bacterium-plasmid combinations.