Pseudomonas aeruginosa mexR and mexEF Antibiotic Efflux Pump Variants Exhibit Increased Virulence

Abstract

Antibiotic-resistant Pseudomonas aeruginosa 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 P. aeruginosa 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 P. aeruginosa virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the mexEF efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in mexR that increased expression of the mexAB-oprM 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 P. aeruginosa, 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.

Low Ciprofloxacin Concentrations Select Multidrug-Resistant Mutants Overproducing Efflux Pumps in Clinical Isolates of Pseudomonas aeruginosa

“…3 ). Supporting this conclusion, notwithstanding some exceptions ( 82 ), it has been described that MexCD-OprJ and MexEF-OprN upregulation entails a reduction in P. aeruginosa virulence ( 41 , 83 , 84 ), due, at least in part, to the implication of these efflux systems in P. aeruginosa ’s quorum sensing response ( 85 , 86 ). Nevertheless, we are aware that other mutations, not analyzed in the current work, may also contribute to these effects on virulence.…”

Advanced transcriptomic analysis reveals the role of efflux pumps and media composition in antibiotic responses ofPseudomonas aeruginosa

“…are indicators of increased pathogenicity in the host in cystic fibrosis (CF) patients ( 49 , 50 ). Further, the mexEF-oprN efflux pump is known to increase virulence in various conditions including CF ( 51 , 52 ). Our study suggests that the mexEF-oprN efflux pump is specific for GlcNAc, Cu, Fe, and Zn.…”

Effects of Sub-Minimum Inhibitory Concentrations of Imipenem and Colistin on Expression of Biofilm-Specific Antibiotic Resistance and Virulence Genes in Acinetobacter baumannii Sequence Type 1894

“…The product of this gene is functionally similar to the MexB-AcrB efflux pump, which confers resistance to β-lactams and cationic antimicrobial peptides. Poole et al (1993) previously reported that deleting the genes encoding the MexAB-OprM efflux pathway in Pseudomonas aeruginosa resulted in hypersensitivity to many antimicrobial compounds [ 50 , 51 , 52 , 53 , 54 ].…”