TY - JOUR
T1 - Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity
AU - Imperi, Francesco
AU - Massai, Francesco
AU - Facchini, Marcella
AU - Frangipani, Emanuela
AU - Visaggio, Daniela
AU - Leoni, Livia
AU - Bragonzi, Alessandra
AU - Visca, Paolo
PY - 2013/4/30
Y1 - 2013/4/30
N2 - 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.
AB - 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.
KW - Antivirulence drug
KW - Cystic fibrosis
KW - Drug repositioning
KW - Iron uptake
KW - Selective optimization of side activities (SOSA) approach
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U2 - 10.1073/pnas.1222706110
DO - 10.1073/pnas.1222706110
M3 - Article
C2 - 23569238
AN - SCOPUS:84876936620
VL - 110
SP - 7458
EP - 7463
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 18
ER -