title: Epistasis buffers the fitness effects of rifampicin- resistance mutations in Pseudomonas aeruginosa.
abstract: Epistatic interactions between resistance mutations in antibiotic-free environments potentially play a crucial role in the spread of resistance in pathogen populations by determining the fitness cost associated with resistance. We used an experimental evolution approach to test for epistatic interactions between 14 different pairs of rifampicin mutations in the pathogenic bacterium Pseudomonas aeruginosa in 42 different rifampicin-free environments. First, we show that epistasis between rifampicin-resistance mutations tends to be antagonistic: the fitness effect of having two mutations is generally smaller than that predicted from the effects of individual mutations on the wild-type. Second, we show that sign epistasis between resistance mutations is both common and strong; most notably, pairs of deleterious resistance mutations often partially or completely compensate for each others' costs, revealing a novel mechanism for compensatory adaptation. These results suggest that antagonistic epistasis between intragenic resistance mutations may be a key determinant of the cost of antibiotic resistance and compensatory adaptation in pathogen populations.
authors.affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. alex.hall@zoo.ox.ac.uk
authors.forename: Alex R
authors.initials: AR
authors.lastname: Hall
authors.forename: R Craig
authors.initials: RC
authors.lastname: MacLean
mesh_terms: D000222:Adaptation, Physiological; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D005075:Biological Evolution; D012321:DNA-Directed RNA Polymerases / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004843:Epistasis, Genetic; D056084:Genetic Fitness; D009154:Mutation / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics*; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D012321:DNA-Directed RNA Polymerases; C105078:RNA polymerase beta subunit; D012293:Rifampin