An alternative approach to the development of new antimicrobials is the inhibition of bacterial virulence, rather than growth. Antivirulence drugs decrease pathogen adaptation to the host environment, hence facilitating the immune system and antibiotics in clearing the infection. The researchers involved in the project have discovered a new antivirulence activity in four “old” FDA-approved drugs, originally developed for the treatment of diseases different from P. aeruginosa infection. The possibility of repurposing these drugs for cystic fibrosis (CF) therapy will be studied in vitro and in animal models, also in combination with antibiotics. The antivirulence activity of the four drugs will be tested in vitro in a collection of 100 Pseudomonas. aeruginosa (Pa)strains isolated from CF patients with intermittent infection and chronic infection. The most promising drugs will be tested for their ability to potentiate antibiotics currently used in CF therapy. Finally, the two most promising drug(s) will be tested in acute and chronic murine models of respiratory Pa infection, also in combination with antibiotics. The assessment of their activity against CF patients strains and possible synergy with antibiotics routinely used in CF therapy will accelerate their delivery to clinical trials.