Inhibiting Quorum Sensing to fight P. aeruginosa/S. aureus biofilms in cystic fibrosis – TARGET-QS

Antimicrobial resistance (AMR) is a public health threat causing 1.2 million deaths worldwide every year. In particular, the ability of bacteria to form biofilms makes them more resistant to antibiotic treatments, which constitutes a major medical challenge. TARGET-QS is a multidisciplinary project aiming to develop new inhibitors effective against resistant bacterial biofilms, by targeting mixed biofilms, composed of P. aeruginosa and S. aureus, two pathogens which cause persistent and often fatal infections in cystic fibrosis patients. Our approach targets Quorum Sensing (QS), a cellular communication system between bacteria, as a novel molecular target. Inhibition of QS prevents biofilm formation and keeps bacteria susceptible to antibiotics, without directly targeting their viability. We have recently developed QS inhibitors that prevent biofilm formation in P. aeruginosa, without cytotoxic effect on lung cells. Based on these promising results, the objective of TARGET-QS is to develop optimized inhibitors as multi-species anti-biofilm agents, following 3 major axes (i) drug-design by QSAR, structure-activity relationships study and validation of the mechanism of action using state-of-the-art techniques to analyze molecule/target interactions (ii) realization of the first preclinical ADME-Tox studies, investigation of their effect on host/pathogen interactions, in particular on the adhesion to epithelial cells and (iii) evaluation of their real time action on mixed biofilms in microfluidic systems. By combining the complementary expertise of chemists (synthesis and modelling), biochemists, microbiologists, biophysicists and clinicians specialized in cystic fibrosis, TARGET-QS will validate QS as a therapeutic target in order to propose innovative treatments for resistant cystic fibrosis related infections, and in a larger perspective, to participate in the global fight against resistant infections that involve bacterial biofilms.