Experimental strategy for the identification and characterization of novel inhibitors of alkylquinolone-dependent quorum sensing regulator in pseudomonas aeruginosa, a promising antibacterial target

Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is an alternative strategy as it is expected to generate less-selective resistance to treatment compared to antibiotics. The MvfR QS system is a promising antivirulence target due to its critical role in inducing the expression of multiple P. aeruginosa virulence systems that promote both acute and chronic infections. In the present study we developed an strategy for the identification and in vitro characterization of novel MvfR inhibitors.A structure-based in silico screening approach was performed following docking studies on M64. Compound 21 was identify as a promising MvfR inhibitor, as it can both reduce in vitro pyocyanin production and HAQs molecules. In order to evaluate in vivo efficacy of novel MvfR inhibitors,the set-up and validation of chronic lung infection in rat was assessed using a clinical strain isolated from the sputum of cystic fibrosis patient.