Early aggressive and maintenance antibiotic therapies prolong cystic fibrosis (CF) patient life, but are not able to eradicate Pseudomonas aeruginosa lung infection. Anti-virulence drugs represent a promising therapeutic option in CF. These new drugs could alleviate the severity of the infection, reduce lung inflammation, and help antibiotics in eradicating the chronic P.aeruginosa lung infection. The long times and high costs required for the evelopment of ???brand new??? anti-virulence drugs can be saved by repurposing ???old??? drugs already used in humans for different purposes. Indeed, we have recently shown that the antimycotic drug flucytosine and the anthelmintic drug niclosamide can be repurposed to suppress P. aeruginosa virulence in vitro and in animal models of infection. However, the old drugs need to be re-formulated for the new clinical application, taking into consideration the peculiarities of CF patients. Objectives 1) To finalize pre-clinical studies concerning flucytosine and niclosamide, by developing and validating inhalable formulations for use in CF therapy. 2) To discovery other drugs with anti-virulence activity against P. aeruginosa. Materials and methods 1) Novel inhalable liquid and dry powders formulations of flucytosine and niclosamide will be developed. In vitro cytotoxicity and activity studies will be performed in lung epithelium cell cultures and on a large number of P. aeruginosa strains isolated from CF patients. Then, toxicity/pharmacokinetic of the developed drug formulations upon inhalation will be evaluated in rats. Finally, the best drug formulations will be validated in a mouse model of lung infection. 2) Purpose-built biosensors able to identify inhibitors of biofilm formation will be used for the screening of 1600 ???old??? drugs. The inhibitory activity of the best anti-biofilm drugs will be validated on P. aeruginosa CF strains.

Anti-virulence therapy against Pseudomonas aeruginosa: identification of antibiofilm drugs and development of inhalable Niclosamide and Flucytosine Formulations

UNGARO, FRANCESCA;SORRENTINO, RAFFAELLA;D'EMMANUELE DI VILLA BIANCA, ROBERTA;DONNARUMMA, ERMINIA;QUAGLIA, FABIANA
2013

Abstract

Early aggressive and maintenance antibiotic therapies prolong cystic fibrosis (CF) patient life, but are not able to eradicate Pseudomonas aeruginosa lung infection. Anti-virulence drugs represent a promising therapeutic option in CF. These new drugs could alleviate the severity of the infection, reduce lung inflammation, and help antibiotics in eradicating the chronic P.aeruginosa lung infection. The long times and high costs required for the evelopment of ???brand new??? anti-virulence drugs can be saved by repurposing ???old??? drugs already used in humans for different purposes. Indeed, we have recently shown that the antimycotic drug flucytosine and the anthelmintic drug niclosamide can be repurposed to suppress P. aeruginosa virulence in vitro and in animal models of infection. However, the old drugs need to be re-formulated for the new clinical application, taking into consideration the peculiarities of CF patients. Objectives 1) To finalize pre-clinical studies concerning flucytosine and niclosamide, by developing and validating inhalable formulations for use in CF therapy. 2) To discovery other drugs with anti-virulence activity against P. aeruginosa. Materials and methods 1) Novel inhalable liquid and dry powders formulations of flucytosine and niclosamide will be developed. In vitro cytotoxicity and activity studies will be performed in lung epithelium cell cultures and on a large number of P. aeruginosa strains isolated from CF patients. Then, toxicity/pharmacokinetic of the developed drug formulations upon inhalation will be evaluated in rats. Finally, the best drug formulations will be validated in a mouse model of lung infection. 2) Purpose-built biosensors able to identify inhibitors of biofilm formation will be used for the screening of 1600 ???old??? drugs. The inhibitory activity of the best anti-biofilm drugs will be validated on P. aeruginosa CF strains.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/597239
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