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.
Highlights
The evolution of antibiotic resistance in pathogenic bacteria is typically accompanied by fitness costs that are expressed in terms of reduced growth rate, competitive ability and virulence [1,2,3]
To that of the rifampicin-sensitive ancestral strain that the resistant mutants were evolved from. These results clearly demonstrate that selection in the absence of antibiotics can rapidly eliminate the substantial fitness cost that is associated with rifampicin resistance for a range of rpoB mutations
The idea that compensatory adaptation eliminates the cost of resistance and allows resistance alleles to effectively persist in bacterial populations has been extensively studied in evolutionary models of antibiotic resistance [2,3,13,55,56,57]
Summary
The evolution of antibiotic resistance in pathogenic bacteria is typically accompanied by fitness costs that are expressed in terms of reduced growth rate, competitive ability and virulence [1,2,3]. We found a relatively small number of compensatory mutations in RNA polymerase, which supports the idea that compensatory mutations are rare [52] This asymmetry is illustrated by the observation that the frequency of repeated independent mutations in rpoB (3/7) was much higher than that in lasR (1/30) among the resistant populations. Three double mutants that carry single lasR mutations in addition to their original rpoB mutations, showed an increased fitness of between 15.6% and 32.3% (electronic supplementary material, figure S1). This suggests that the fitness benefit associated with lasR mutations was likely to be comparable to, or greater than, the benefit associated with compensatory mutations, except when the cost of resistance was very large. It is conceivable that the different amounts of time spent by the various strains in the stationary phase could have contributed to these differences in the mutational spectrum
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
More From: Proceedings of the Royal Society B: Biological Sciences
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.