title: Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity.
abstract: Although antibiotic resistance represents a public health emergency, the pipeline of new antibiotics is running dry. Repurposing of old drugs for new clinical applications is an attractive strategy for drug development. We used the bacterial pathogen Pseudomonas aeruginosa as a target for the screening of antivirulence activity among marketed drugs. We found that the antimycotic agent flucytosine inhibits the expression of the iron-starvation σ-factor PvdS, thereby repressing the production of major P. aeruginosa virulence factors, namely pyoverdine, PrpL protease, and exotoxin A. Flucytosine administration at clinically meaningful dosing regimens suppressed P. aeruginosa pathogenicity in a mouse model of lung infection. The in vitro and in vivo activity of flucytosine against P. aeruginosa, combined with its desirable pharmacological properties, paves the way for clinical trials on the anti-P. aeruginosa efficacy of flucytosine in humans.
authors.affiliation: Department of Biology and Biotechnology C. Darwin, Sapienza University of Rome, 000185 Rome, Italy. francesco.imperi@uniroma1.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Imperi
authors.forename: Francesco
authors.initials: F
authors.lastname: Massai
authors.forename: Marcella
authors.initials: M
authors.lastname: Facchini
authors.forename: Emanuela
authors.initials: E
authors.lastname: Frangipani
authors.forename: Daniela
authors.initials: D
authors.lastname: Visaggio
authors.forename: Livia
authors.initials: L
authors.lastname: Leoni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Visca
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005437:Flucytosine / Q000494:pharmacology* / Q000627:therapeutic use; D005472:Fluorouracil / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000096:biosynthesis; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D012808:Sigma Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014774:Virulence / Q000187:drug effects / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D001426:Bacterial Proteins; D009842:Oligopeptides; C093593:PvdS protein, Pseudomonas aeruginosa; D012808:Sigma Factor; C042453:pyoverdin; D005437:Flucytosine; D005472:Fluorouracil