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

D'Angelo, Francesca; Baldelli, Valerio; Halliday, Nigel; Pantalone, Paolo; Polticelli, Fabio; Fiscarelli, Ersilia; Williams, Paul; Visca, Paolo; Leoni, Livia; Rampioni, Giordano

Authors

Francesca D'Angelo

Valerio Baldelli

Nigel Halliday

Paolo Pantalone

Fabio Polticelli

Ersilia Fiscarelli

Paul Williams

Paolo Visca

Livia Leoni

Giordano Rampioni



Abstract

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.

Journal Article Type Article
Publication Date Oct 10, 2018
Journal Antimicrobial Agents and Chemotherapy
Print ISSN 0066-4804
Electronic ISSN 1098-6596
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 62
Issue 11
Article Number e01296-18
Institution Citation D'Angelo, F., Baldelli, V., Halliday, N., Pantalone, P., Polticelli, F., Fiscarelli, E., …Rampioni, G. (2018). Identification of FDA-approved drugs as antivirulence agents targeting the pqs quorum sensing system of Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 62(11), doi:10.1128/aac.01296-18
DOI https://doi.org/10.1128/aac.01296-18
Keywords Pharmacology (medical); Pharmacology; Infectious Diseases
Publisher URL https://aac.asm.org/content/62/11/e01296-18.long

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