The Sociality and Evolution of Plasmid-Mediated Antimicrobial Resistance

Overuse and misuse of antibiotics has led to the global spread of antimicrobial resistance, threatening our ability to treat bacterial infections. The horizontal acquisition of multidrug resistance (MDR) plasmids, from other bacterial lineages, has been instrumental in spreading resistance. Newly acquired plasmids are often poorly adapted to hosts causing intragenomic conflicts, reducing the competitiveness of plasmid-carrying strains. Costs can be overcome by positive selection for plasmid-encoded adaptive traits in the short-term, or ameliorated by compensatory evolution in the long-term. How the selection and adaptation of MDR plasmids varies with antibiotic treatment remains unclear. First, I demonstrate that the selective conditions for the maintenance of an MDR plasmid are dependent upon the sociality of resistance it encodes. Selection for efflux of antibiotics, a selfish trait, occurred at very low concentrations of antibiotic, far below the minimum inhibitory concentration of sensitive plasmid-free strain. In contrast, selection for inactivation of antibiotics, a cooperative trait, increased the amount of antibiotic required to select for the MDR plasmid, allowing sensitive plasmid-free bacteria to survive high levels of antibiotic. These selection dynamics were only accurately predicted when mathematical models included the mechanistic details of antibiotic resistance. Secondly, I show that the trajectory of evolution following MDR plasmid acquisition varies with antibiotic treatment. Tetracycline treatment favoured a distinct coevolutionary trajectory of chromosomal resistance mutations coupled with plasmid mutations impairing plasmid-borne resistance. This led to high-level, low-cost antibiotic resistance, but also produced an integrated genome of co-dependent replicons that may limit the onward spread of co-adapted MGEs to other lineages. This evolutionary trajectory was strikingly repeatable across independently evolving populations despite the emergence of multiple competing lineages within populations. The results presented here demonstrate that the interaction between positive selection and compensatory evolution can help to explain the persistence of MDR plasmids in the clinic and the environment.