Abstract
Bacterial cells have evolved the capacity to communicate between each other via small diffusible chemical signals termed autoinducers. Pseudomonas aeruginosa is an opportunistic pathogen involved, among others, in cystic fibrosis complications. Virulence of P. aeruginosa relies on its ability to produce a number of autoinducers, including 4-hydroxy-2-alkylquinolines (HAQ). In a cell density-dependent manner, accumulated signals induce the expression of multiple targets, especially virulence factors. This phenomenon, called quorum sensing, promotes bacterial capacity to cause disease. Furthermore, P. aeruginosa possesses many multidrug efflux pumps conferring adaptive resistance to antibiotics. Activity of some of these efflux pumps also influences quorum sensing. The present study demonstrates that the MexEF-OprN efflux pump modulates quorum sensing through secretion of a signalling molecule belonging to the HAQ family. Moreover, activation of MexEF-OprN reduces virulence factor expression and swarming motility. Since MexEF-OprN can be activated in infected hosts even in the absence of antibiotic selective pressure, it could promote establishment of chronic infections in the lungs of people suffering from cystic fibrosis, thus diminishing the immune response to virulence factors. Therapeutic drugs that affect multidrug efflux pumps and HAQ-mediated quorum sensing would be valuable tools to shut down bacterial virulence.
Highlights
Chronic infections caused by the opportunistic pathogen Pseudomonas aeruginosa are strongly associated with cystic fibrosis (CF)-related complications such as lung damage and airway obstruction [1]
OprN fails to convert most HHQ into Pseudomonas Quinolone Signal (PQS) To further characterize the effects of MexEF-OprN efflux pump activation on quorum sensing (QS), the concentrations of the best known MvfRdependent QS signaling molecules were compared between the wild-type P. aeruginosa strain PA14 and its isogenic mexS2 mutant (MGL01), which represents an nfxC phenotype
The present study shows that the MexEF-OprN efflux pump exports the PQS precursor, HHQ
Summary
Chronic infections caused by the opportunistic pathogen Pseudomonas aeruginosa are strongly associated with cystic fibrosis (CF)-related complications such as lung damage and airway obstruction [1]. These complications result from the exacerbated inflammation associated with the chronic infection of cystic fibrotic lungs [2]. In P. aeruginosa, activation of the MexEF-OprN RND-type efflux pump gives rise to, among others, chloramphenicol, fluoroquinolones, trimethoprim and triclosan resistance [7]. This efflux pump is encoded by the mexEF-oprN operon and is positively controlled by MexT, a transcriptional regulator belonging to the LysR family [8,9]. MexS presents homologies with Zn2+-dependent oxidoreductases/deshydrogenases, some of which associated with amino acid metabolism
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