title: New life for an old drug: the anthelmintic drug niclosamide inhibits Pseudomonas aeruginosa quorum sensing.
abstract: The need for novel antibacterial strategies and the awareness of the importance of quorum sensing (QS) in bacterial infections have stimulated research aimed at identifying QS inhibitors (QSIs). However, clinical application of QSIs identified so far is still distant, likely due to their unsuitability for use in humans. A promising way to overcome this problem is searching for anti-QS side activity among the thousands of drugs approved for clinical use in the treatment of different diseases. Here, we applied this strategy to the search for QSIs, by screening a library of FDA-approved compounds for their ability to inhibit the QS response in the Gram-negative pathogen Pseudomonas aeruginosa. We found that the anthelmintic drug niclosamide strongly inhibits the P. aeruginosa QS response and production of acyl-homoserine lactone QS signal molecules. Microarray analysis showed that niclosamide affects the transcription of about 250 genes, with a high degree of target specificity toward the QS-dependent regulon. Phenotypic assays demonstrated that niclosamide suppresses surface motility and production of the secreted virulence factors elastase, pyocyanin, and rhamnolipids, and it reduces biofilm formation. In accordance with the strong antivirulence activity disclosed in vitro, niclosamide prevented P. aeruginosa pathogenicity in an insect model of acute infection. Besides the finding that an FDA-approved drug has a promising antivirulence activity against one of the most antibiotic-resistant bacterial pathogens, this work provides a proof of concept that a lateral anti-QS activity can be detected among drugs already used in humans, validating a new approach to identify QSIs that could easily move into clinical applications.
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Imperi
authors.forename: Francesco
authors.initials: F
authors.lastname: Massai
authors.forename: Cejoice
authors.initials: C
authors.lastname: Ramachandran Pillai
authors.forename: Francesca
authors.initials: F
authors.lastname: Longo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zennaro
authors.forename: Giordano
authors.initials: G
authors.lastname: Rampioni
authors.forename: Paolo
authors.initials: P
authors.lastname: Visca
authors.forename: Livia
authors.initials: L
authors.lastname: Leoni
mesh_terms: D054742:Acyl-Butyrolactones / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000923:Anticestodal Agents / Q000494:pharmacology*; D000969:Antinematodal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D055808:Drug Discovery; D006017:Glycolipids / Q000378:metabolism; D009534:Niclosamide / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000378:metabolism; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D011710:Pyocyanine / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects*; D037521:Virulence Factors / Q000235:genetics
chemical_list: D054742:Acyl-Butyrolactones; D000900:Anti-Bacterial Agents; D000923:Anticestodal Agents; D000969:Antinematodal Agents; D006017:Glycolipids; D037521:Virulence Factors; C418382:rhamnolipid; D009534:Niclosamide; D011710:Pyocyanine; D010196:Pancreatic Elastase