Evolutionary loss of an antibiotic efflux pump increases Pseudomonas aeruginosa quorum sensing mediated virulence in vivo

Sheryl E. Fernandes, Humberto Ortega, Mylene Vaillancourt, Anna Clara M. Galdino, Aleksandr Stotland, Kyu Shik Mun, Diane Aguilar, Yohei Doi, Janet S. Lee, Elizabeth B. Burgener, Jeffrey E. Barrick, Jeffrey W. Schertzer and Peter Jorth ()
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Sheryl E. Fernandes: Cedars-Sinai Medical Center
Humberto Ortega: Binghamton University
Mylene Vaillancourt: Cedars-Sinai Medical Center
Anna Clara M. Galdino: Cedars-Sinai Medical Center
Aleksandr Stotland: Cedars-Sinai Medical Center
Kyu Shik Mun: Cedars-Sinai Medical Center
Diane Aguilar: Cedars-Sinai Medical Center
Yohei Doi: University of Pittsburgh
Janet S. Lee: Washington University School of Medicine in St. Louis
Elizabeth B. Burgener: Children’s Hospital Los Angeles
Jeffrey E. Barrick: The University of Texas at Austin
Jeffrey W. Schertzer: Binghamton University
Peter Jorth: Cedars-Sinai Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Antibiotic resistance is a threat to human health, yet recent work highlights how loss of resistance may drive pathogenesis in some bacteria. In two recent studies, we found that β-lactam antibiotics and nutrient stresses faced during infection selected for genetic inactivation of the Pseudomonas aeruginosa antibiotic efflux pump mexEFoprN. Unexpectedly, efflux pump mutations increased P. aeruginosa virulence during infection; however, neither the prevalence of mexEFoprN inactivating mutations in real human infections, nor the mechanisms driving increased virulence of efflux pump mutants are known. We hypothesized that human infection would select for virulence enhancing mutations. Using genome sequencing of clinical isolates, we show that mexEFoprN efflux pump inactivating mutations are enriched in P. aeruginosa isolates from cystic fibrosis infections relative to isolates from acute respiratory infections. Combining RNA-seq, metabolomics, genetic approaches, and infection models we show that efflux pump mutants have elevated quorum sensing driven expression of elastase and rhamnolipids which increase P. aeruginosa virulence during acute and chronic infections. Restoration of the efflux pump in a representative respiratory isolate and the notorious cystic fibrosis Liverpool epidemic strain reduced their virulence. These findings suggest that mutations inactivating antibiotic resistance mechanisms could lead to greater patient mortality and morbidity.

Date: 2025
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DOI: 10.1038/s41467-025-63284-7

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