ArticlePLoS biology2022
Hypermutator strains of Pseudomonas aeruginosa reveal novel pathways of resistance to combinations of cephalosporin antibiotics and beta-lactamase inhibitors.
Article in PLoS biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 19 citations in OpenAlex.
- High resolution cryo-EM structure of theJournal of structural biology: X · 2026Article
- A genome-wide screen inJournal of bacteriology · 2026Article
- From nature to clinic: tracking genetic and environmental drivers of Stenotrophomonas maltophilia pathogenicity.Archives of microbiology · 2026Review
- Clearance of hypermutator XDRASM case reports · 2026Article
- Mutant prevention concentrations and phenotypic and genomic profiling of first-step resistance mechanisms to classical and novel β-lactams inAntimicrobial agents and chemotherapy · 2025Article
- Article
- Transcriptional diversification in a human-adapting zoonotic pathogen drives niche-specific evolution.Nature communications · 2025Article
- The mutational landscape of Bacillus subtilis conditional hypermutators shows how proofreading skews DNA polymerase error rates.Nucleic acids research · 2025Article
- Mutational signature analysis predicts bacterial hypermutation and multidrug resistance.Nature communications · 2025Article
- Ceftazidime-Induced Overexpression of MexJK-OprM Confers Resistance to Ceftolozane/Tazobactam in an Isolate ofInfection and drug resistance · 2025Article
- Genomic epidemiology and ceftazidime-avibactam high-level resistance mechanisms ofEmerging microbes & infections · 2024Article
- Efflux pump-mediated resistance to new beta lactam antibiotics in multidrug-resistant gram-negative bacteria.Communications medicine · 2024Review
- The role of hypermutation and collateral sensitivity in antimicrobial resistance diversity ofmBio · 2024Article
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Authors and funding
8 authors at 2 institutions in 1 country.
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Abstract
Hypermutation due to DNA mismatch repair (MMR) deficiencies can accelerate the development of antibiotic resistance in Pseudomonas aeruginosa. Whether hypermutators generate resistance through predominantly similar molecular mechanisms to wild-type (WT) strains is not fully understood. Here, we show that MMR-deficient P. aeruginosa can evolve resistance to important broad-spectrum cephalosporin/beta-lactamase inhibitor combination antibiotics through novel mechanisms not commonly observed in WT lineages. Using whole-genome sequencing (WGS) and transcriptional profiling of isolates that underwent in vitro adaptation to ceftazidime/avibactam (CZA), we characterized the detailed sequence of mutational and transcriptional changes underlying the development of resistance. Surprisingly, MMR-deficient lineages rapidly developed high-level resistance (>256 μg/mL) largely without corresponding fixed mutations or transcriptional changes in well-established resistance genes. Further investigation revealed that these isolates had paradoxically generated an early inactivating mutation in the mexB gene of the MexAB-OprM efflux pump, a primary mediator of CZA resistance in P. aeruginosa, potentially driving an evolutionary search for alternative resistance mechanisms. In addition to alterations in a number of genes not known to be associated with resistance, 2 mutations were observed in the operon encoding the RND efflux pump MexVW. These mutations resulted in a 4- to 6-fold increase in resistance to ceftazidime, CZA, cefepime, and ceftolozane-tazobactam when engineered into a WT strain, demonstrating a potentially important and previously unappreciated mechanism of resistance to these antibiotics in P. aeruginosa. Our results suggest that MMR-deficient isolates may rapidly evolve novel resistance mechanisms, sometimes with complex dynamics that reflect gene inactivation that occurs with hypermutation. The apparent ease with which hypermutators may switch to alternative resistance mechanisms for which antibiotics have not been developed may carry important clinical implications.
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