Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa

Abstract

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 QS system of the human pathogen by screening a library of 1,600 U.S. Food and Drug Administration-approved drugs. Phenotypic characterization of engineered strains and molecular docking demonstrated that the antifungal drugs clotrimazole and miconazole, as well as an antibacterial compound active against Gram-positive pathogens, clofoctol, inhibit the system, probably by targeting the transcriptional regulator PqsR. The most active inhibitor, clofoctol, specifically inhibited the expression of-controlled virulence traits in , such as pyocyanin production, swarming motility, biofilm formation, and expression of genes involved in siderophore production. Moreover, clofoctol protected larvae from infection and inhibited the QS system in 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 lung infections.

Galleria mellonella as a consolidated in vivo model hosts: New developments in antibacterial strategies and novel drug testing

“…Furthermore, the treatment with clofoctol led to a larvae survival percentage similar to that observed with the ΔpqsR mutant. Overall, these data demonstrate that clofoctol attenuates P. aeruginosa PAO1 lethality in G. mellonella [65].…”

4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases

“…The spread of multidrug-resistant (MDR) Gram-negative bacteria is a recognised public-health issue, compromising the efficacious treatment of bacterial infections, and becoming a leading cause of death worldwide [1]. Although there has recently been a resurgence in antibiotic drug discovery and new targets, mechanisms and molecular entities have been addressed [2][3][4], the need for continuous investment in antibiotic-drug development is necessary. At present, β-lactams remain the most commonly used antibiotics in bacterial infections worldwide.…”

Targeting virulence factors as an antimicrobial approach: Pigment inhibitors

“…Rampioni's group described the identification of new inhibitors of the human pathogen P. aeruginosa QS system by screening a library of 1600 FDA‐approved drugs. The antibiotic clofoctol ( 72 ) presented the most active inhibition of virulence in P. aeruginosa by targeting the transcriptional regulator PqsR, which specifically inhibits the expression of pqs ‐controlled QS virulence traits, such as pyocyanin production, swarming motility, and biofilm formation . Secnidazole ( 73 ), a known nitroimidazole drug, has been used for the treatment of many infections caused by anaerobic pathogens and has shown a powerful inhibitory effect on P. aeruginosa virulence factors in recent studies .…”

“…The antibiotic clofoctol (72) presented the most active inhibition of virulence in P. aeruginosa by targeting the transcriptional regulator PqsR, which specifically inhibits the expression of pqs-controlled QS virulence traits, such as pyocyanin production, swarming motility, and biofilm formation. 154 Secnidazole (73), a known nitroimidazole drug, has been used for the treatment of many infections caused by anaerobic pathogens and has shown a powerful inhibitory effect on P. aeruginosa virulence factors in recent studies. 155 The antidiabetic agent metformin (74) and the Chinese herb phillyrin (75) were also identified to significantly reduce the production of the pigments violacein and pyocyanin in recent studies.…”