<i>Pseudomonas aeruginosa</i> <i>mexR</i> and <i>mexEF</i> Antibiotic Efflux Pump Variants Exhibit Increased Virulence

• Main Authors: Mylene Vaillancourt (Author), Sam P. Limsuwannarot (Author), Catherine Bresee (Author), Rahgavi Poopalarajah (Author), Peter Jorth (Author)
• Format: Book
• Published: MDPI AG, 2021-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Antibiotic-resistant <i>Pseudomonas aeruginosa</i> infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i>P. aeruginosa</i> virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i>P. aeruginosa</i> virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i>mexEF</i> efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i>mexR</i> that increased expression of the <i>mexAB-oprM</i> efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i>P. aeruginosa</i>, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution.

Item Description

10.3390/antibiotics10101164
2079-6382