Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity

Francesco Imperi, Francesco Massai, Marcella Facchini, Emanuela Frangipani, Daniela Visaggio, Livia Leoni, Alessandra Bragonzi, Paolo Visca

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)7458-7463
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number18
DOIs
Publication statusPublished - Apr 30 2013

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Keywords

  • Antivirulence drug
  • Cystic fibrosis
  • Drug repositioning
  • Iron uptake
  • Selective optimization of side activities (SOSA) approach

ASJC Scopus subject areas

  • General

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