title: The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa.
abstract: Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR. Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings.
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK Institute of Science and Technology Austria, Klosterneuburg, Austria qin.qi06@alumni.imperial.ac.uk.
authors.forename: Qin
authors.identifier: http://orcid.org/0000-0002-6148-2416
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland.
authors.forename: Macarena
authors.initials: M
authors.lastname: Toll-Riera
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Heilbron
authors.affiliation: Department of Plant Sciences, University of Oxford, Oxford, UK.
authors.forename: Gail M
authors.identifier: http://orcid.org/0000-0003-3882-4438
authors.initials: GM
authors.lastname: Preston
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK craig.maclean@zoo.ox.ac.uk.
authors.forename: R Craig
authors.identifier: http://orcid.org/0000-0002-7941-813X
authors.initials: RC
authors.lastname: MacLean
mesh_terms: D000220:Adaptation, Biological; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D056084:Genetic Fitness; D023281:Genomics; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D012293:Rifampin
keywords: compensatory adaptation; experimental evolution; general adaptation; rifampicin resistance; whole-genome sequencing