Repurposing the antimycotic drug flucytosine for suppression of<i>Pseudomonas aeruginosa</i>pathogenicity

DOI Web Site 被引用文献3件
  • Francesco Imperi
    Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, 000185 Rome, Italy;
  • Francesco Massai
    Department of Sciences, University “Roma Tre”, 00146 Rome, Italy; and
  • Marcella Facchini
    Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy
  • Emanuela Frangipani
    Department of Sciences, University “Roma Tre”, 00146 Rome, Italy; and
  • Daniela Visaggio
    Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, 000185 Rome, Italy;
  • Livia Leoni
    Department of Sciences, University “Roma Tre”, 00146 Rome, Italy; and
  • Alessandra Bragonzi
    Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy
  • Paolo Visca
    Department of Sciences, University “Roma Tre”, 00146 Rome, Italy; and

説明

<jats:p>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<jats:italic>Pseudomonas aeruginosa</jats:italic>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<jats:italic>P. aeruginosa</jats:italic>virulence factors, namely pyoverdine, PrpL protease, and exotoxin A. Flucytosine administration at clinically meaningful dosing regimens suppressed<jats:italic>P. aeruginosa</jats:italic>pathogenicity in a mouse model of lung infection. The in vitro and in vivo activity of flucytosine against<jats:italic>P. aeruginosa,</jats:italic>combined with its desirable pharmacological properties, paves the way for clinical trials on the anti-<jats:italic>P. aeruginosa</jats:italic>efficacy of flucytosine in humans.</jats:p>

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