RT Journal Article
SR Electronic
T1 Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the <em>pqs</em> Quorum-Sensing System of <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span>
JF Antimicrobial Agents and Chemotherapy
JO Antimicrob. Agents Chemother.
FD American Society for Microbiology
SP e01296-18
DO 10.1128/AAC.01296-18
VO 62
IS 11
A1 D'Angelo, Francesca
A1 Baldelli, Valerio
A1 Halliday, Nigel
A1 Pantalone, Paolo
A1 Polticelli, Fabio
A1 Fiscarelli, Ersilia
A1 Williams, Paul
A1 Visca, Paolo
A1 Leoni, Livia
A1 Rampioni, Giordano
YR 2018
UL http://aac.asm.org/content/62/11/e01296-18.abstract
AB The long-term use of antibiotics has led to the emergence of multidrug-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 U.S. Food and Drug Administration-approved drugs. Phenotypic characterization of ad hoc engineered strains and in silico molecular docking demonstrated that the antifungal drugs clotrimazole and miconazole, as well as 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.