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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.

Original publication

DOI

10.1111/j.1558-5646.2011.01302.x

Type

Journal article

Journal

Evolution

Publication Date

08/2011

Volume

65

Pages

2370 - 2379

Keywords

Adaptation, Physiological, Anti-Bacterial Agents, Biological Evolution, DNA-Directed RNA Polymerases, Drug Resistance, Microbial, Epistasis, Genetic, Genetic Fitness, Mutation, Pseudomonas aeruginosa, Rifampin