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<p>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 <i>Pseudomonas aeruginosa</i> antibiotic efflux pump <i>mexEFoprN</i>. Unexpectedly, efflux pump mutations increased <i>P. aeruginosa</i> virulence during infection; however, neither the prevalence of <i>mexEFoprN</i> 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 <i>mexEFoprN</i> efflux pump inactivating mutations are enriched in <i>P. aeruginosa</i> 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 <i>P. aeruginosa</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • 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,
  • Peter Jorth

摘要

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.