Resistance variation and bacterial interactions shape adaptation of a genetically diverse pathogen population to...

Antimicrobial resistance (AMR) poses a major threat to global human health. The emergence and spread of AMR is usually studied for single pathogen lineages. Therefore, we currently have only limited knowledge on the causes and dynamics of resistance evolution in polymicrobial or multistrain infections that involve different pathogen species or strains, respectively, even though these kinds of infections are widespread. To address these current knowledge gaps, we here used the opportunistic human pathogen Pseudomonas aeruginosa as a model to investigate how AMR evolves in populations with different genetically distinct strains (multistrain communities). By using controlled evolution experiments, extensive phenotyping and genome sequence analysis, we demonstrate that the response to antibiotic selection is shaped by a combination of strain-specific resistance profiles, ecological interactions between strains, and metapopulation structure. Moreover, the likelihood of de novo resistance evolution varied in dependence on mutation rates for resistance. A second independent evolution experiment emphasized the central role of strain variation and strain-strain interactions during adaptation. We conclude that AMR evolution in genetically diverse pathogen populations is driven by the interplay of ecological and evolutionary dynamics, thus deserving particular attention during treatment of polymicrobial infections.