Over the last decades, massive misuse of antibiotics (ATB) prompted the emergence of resistances in many microorganisms such as ESKAPEE pathogens responsible for various nosocomial infections. Indeed, the selective pressure on viability induced by conventional antimicrobial molecules promotes resistant strain multiplication. The development of anti-virulence agents (AVA) targeting bacteria pathogenicity without affecting their growth seems to be a new interesting therapeutic strategy. Such AVA could potentiate the host’s immune system response in monotherapy and restore efficiency of conventional ATB in combination therapy. The quorum sensing (QS), referring to the communication systems of bacteria, constitutes a pool of promising pharmacological targets for the development of AVA. Quorum quenching could disrupt, especially in P. aeruginosa, intra/inter-species protective interactions that stimulate virulence pathways (biofilm or pyocyanin production). Pseudomonas Quinolone Signal receptor (PqsR) that regulates virulence gene expression in response to cell density or environmental changes once activated by its natural ligand (PQS), has recently emerged as an interesting key protein to lock. Among PqsR antagonists described in the literature, the 6-nitro-2-heptyl-4(1H)-quinolone-3-carboxamide inhibits pyocyanin production with an IC50 of 2 µM in P. aeruginosa PA14 strain. Taking this into account, we aim to develop a new family of 2-heteroaryl-4-quinolones potentially active against P. aeruginosa as quorum quenchers. The synthesis pathways based on pallado-catalyzed coupling reactions, but also the physicochemical and biological evaluations of these compounds (intrinsic antibiotic and anti-virulence properties) will be described in the presentation.

Anti-virulence 2-heteroaryl-4-quinolone agents to tackle multi-drug resistant Pseudomonas aeruginosa bacteria

ACS Fall 2021

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