ArticleMolecular biology and evolution2021
The Genomic Basis of Rapid Adaptation to Antibiotic Combination Therapy in Pseudomonas aeruginosa.
Article in Molecular biology and evolution, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Forecasting Multitrait Resistance Evolution under Antibiotic Stress.Molecular biology and evolution · 2026Article
- Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope.Nature communications · 2026Article
- Adaptive microevolution in CC17Frontiers in cellular and infection microbiology · 2026Article
- Novel therapeutic strategies targeting infections caused by P. aeruginosa biofilm.Molecular biology reports · 2025Review
- Genome and transcriptomic analysis of the adaptation ofComputational and structural biotechnology journal · 2024Review
- Article
- Mutators can drive the evolution of multi-resistance to antibiotics.PLoS genetics · 2023Article
- Antibacterial activity of metal-phenanthroline complexes against multidrug-resistant Irish clinical isolates: a whole genome sequencing approach.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2023Article
- The Effects of Antibiotic Combination Treatments on Pseudomonas aeruginosa Tolerance Evolution and Coexistence with Stenotrophomonas maltophilia.Microbiology spectrum · 2022Article
- Evolutionary History and Strength of Selection Determine the Rate of Antibiotic Resistance Adaptation.Molecular biology and evolution · 2022Article
- Antibiotic Resistance in Pseudomonas.Advances in experimental medicine and biology · 2022Article
- Leveraging laboratory and clinical studies to design effective antibiotic combination therapy.Current opinion in microbiology · 2021Review
- Bottleneck size and selection level reproducibly impact evolution of antibiotic resistance.Nature ecology & evolution · 2021Article
- Article
- Article
- Coming from the Wild: Multidrug Resistant Opportunistic Pathogens Presenting a Primary, Not Human-Linked, Environmental Habitat.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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