期刊
MOLECULAR BIOLOGY AND EVOLUTION
卷 38, 期 2, 页码 449-464出版社
OXFORD UNIV PRESS
DOI: 10.1093/molbev/msaa233
关键词
Pseudomonas aeruginosa; antibiotic resistance; combination therapy; efflux pumps; intergenic variants
资金
- German Science Foundation (DFG) [SCHU 1415/12, EXC 22167-39088401]
- Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG)
- International Max-Planck-Research School for Evolutionary Biology
- Max-Planck Society
Combination therapy is commonly used to reduce resistance evolution in infectious diseases, but its efficacy against Pseudomonas aeruginosa has been unclear. Whole-genome sequencing of evolved populations showed that changes in efflux pump regulation are a favored mechanism of resistance, with intergenic variants potentially playing a regulatory role in bacterial resistance evolution.
Combination therapy is a common antibiotic treatment strategy that aims at minimizing the risk of resistance evolution in several infectious diseases. Nonetheless, evidence supporting its efficacy against the nosocomial opportunistic pathogen Pseudomonas aeruginosa remains elusive. Identification of the possible evolutionary paths to resistance in multidrug environments can help to explain treatment outcome. For this purpose, we here performed whole-genome sequencing of 127 previously evolved populations of P. aeruginosa adapted to sublethal doses of distinct antibiotic combinations and corresponding single-drug treatments, and experimentally characterized several of the identified variants. We found that alterations in the regulation of efflux pumps are the most favored mechanism of resistance, regardless of the environment. Unexpectedly, we repeatedly identified intergenic variants in the adapted populations, often with no additional mutations and usually associated with genes involved in efflux pump expression, possibly indicating a regulatory function of the intergenic regions. The experimental analysis of these variants demonstrated that the intergenic changes caused similar increases in resistance against single and multidrug treatments as those seen for efflux regulatory gene mutants. Surprisingly, we could find no substantial fitness costs for a majority of these variants, most likely enhancing their competitiveness toward sensitive cells, even in antibiotic-free environments. We conclude that the regulation of efflux is a central target of antibiotic-mediated selection in P. aeruginosa and that, importantly, changes in intergenic regions may represent a usually neglected alternative process underlying bacterial resistance evolution, which clearly deserves further attention in the future.
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