New life for an old drug: the anthelmintic drug niclosamide inhibits Pseudomonas aeruginosa quorum sensing-
Francesco Imperi 1, Francesco Massai 2, Cejoice Ramachandran Pillai 2, Francesca Longo 2, Elisabetta Zennaro 2, Giordano Rampioni 2, Paolo Visca 2 and Livia Leoni 2,#
Author Affiliations: <SUP>1</SUP> Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy <SUP>2</SUP> Department of Biology, University Roma Tre, Rome, Italy
The need for novel antibacterial strategies and the awareness of the importance of quorum sensing (QS) in bacterial infections has 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 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 towards the QS-dependent regulon. Phenotypic assays demonstrated that niclosamide suppresses surface motility, production of secreted virulence factors elastase, pyocyanin and rhamnolipids, and reduces biofilm formation. In accordance with the strong anti-virulence 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 anti-virulence 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.
#Corresponding author. Mailing address: Department of Biology, University “Roma Tre”, Viale G. Marconi 446, 00146 Rome, Italy. Phone: +39.6.5517.6318. Fax: +39.6.5517.6321. E-mail: firstname.lastname@example.org
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