Development of new anti-virulence agents to tackle multi-resistant Pseudomonas aeruginosa.

The multi-resistant opportunistic bacterium Pseudomonas aeruginosa has been identified by the WHO as one of the most threatening pathogens of our time, and a priority for the development of new treatments. Biofilms produced by this micro-organism act as protective barriers. They increase both its pathogenicity via a persistence towards the immune system and its resistance to antibiotics. Biofilm formation is coordinated by the Quorum Sensing (QS) that is a bacterial communication network responsible for virulence pathways expression according to the population density. In P. aeruginosa specific QS system pqs, the transcription factor PqsR regulates the activation of virulence-related genes via recognition of its auto-inducer PQS (Pseudomonas Quinolone Signal). This circuit stimulates the secretion of virulence factors like pyocyanin as well as the establishment of biofilms. Therefore, the development of non-bactericidal agents that disrupt QS connections appears as a promising alternative to conventional medicines, without creating selection pressure issues. These new anti-virulence agents (AVAs) could restore the efficacy of antibiotics when used in combination therapy. In particular, the design of AVAs that inhibit PqsR appears to be a sustainable approach to combat P. aeruginosa specifically. Bi-aromatic PqsR inhibitors possessing a 4-aminoquinoline moiety have been described in the literature. Meanwhile, our team recently discovered a series of 2-heteroaryl-4-quinolones that display interesting anti-biofilm and anti-pyocyanin activities. We now aim at developing a family of 2-heteroaryl-4-aminoquinolines as new AVAs potentially inhibiting PqsR. The synthesis as well as the physicochemical and biological evaluation of those novel molecules will be described in the poster.