title: Epistasis between antibiotic resistance mutations and genetic background shape the fitness effect of resistance across species of Pseudomonas.
abstract: Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase (rpoB) across eight strains that span the diversity of the genus Pseudomonas We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across three strains of Pseudomonas Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds.
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK t.vogwill@imperial.ac.uk.
authors.forename: T
authors.identifier: 0000-0003-1044-6623
authors.initials: T
authors.lastname: Vogwill
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK Université Aix-Marseille-CNRS, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: Kojadinovic
authors.affiliation: Department of Zoology, University of Oxford, Oxford, UK craig.maclean@zoo.ox.ac.uk.
authors.forename: R C
authors.initials: RC
authors.lastname: MacLean
mesh_terms: D012321:DNA-Directed RNA Polymerases / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004843:Epistasis, Genetic; D015964:Gene Expression Regulation, Bacterial; D009154:Mutation; D010802:Phylogeny; D011549:Pseudomonas / Q000187:drug effects* / Q000235:genetics*; D012293:Rifampin / Q000494:pharmacology
chemical_list: D012321:DNA-Directed RNA Polymerases; D012293:Rifampin
keywords: Pseudomonas; antibiotic resistance; fitness costs; genetic background