Identification of FDA-approved drugs as antivirulence agents targeting the pqs quorum sensing system of Pseudomonas aeruginosa [Mechanisms of Action]

The long-term use of antibiotics has led to the emergence of multi-drug-resistant bacteria. A promising strategy to combat bacterial infections aims at hampering their adaptability to the host environment without affecting growth. In this context, the intercellular communication system quorum sensing (QS), which controls virulence factor production and biofilm formation in diverse human pathogens, is considered an ideal target.

Here we describe the identification of new inhibitors of the pqs QS system of the human pathogen Pseudomonas aeruginosa, by screening a library of 1,600 FDA-approved drugs. Phenotypic characterization of ad hoc engineered strains and in silico molecular docking demonstrated that the antifungal drugs clotrimazole and miconazole, and an antibacterial compound active against Gram-positive pathogens, clofoctol, inhibit the pqs system, probably by targeting the transcriptional regulator PqsR. The most active inhibitor, clofoctol, specifically inhibited the expression of pqs-controlled virulence traits in P. aeruginosa, such as pyocyanin production, swarming motility, biofilm formation, and expression of genes involved in siderophore production. Moreover, clofoctol protected Galleria mellonella larvae from P. aeruginosa infection and inhibited the pqs QS system in P. aeruginosa isolates from cystic fibrosis patients. Notably, clofoctol is already approved for clinical treatment of pulmonary infections caused by Gram-positive bacterial pathogens, hence this drug has considerable clinical potential as an antivirulence agent for the treatment of P. aeruginosa lung infections.

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