Bacterial infections are on the road back to the top leading cause-of-death in the world. Over half a century of massive misuse of antibiotics (ATBs) has driven the emergence of MultiDrug Resistant (MDR) pathogens. Among them, Pseudomonas aeruginosa was designated by the WHO as a critical priority that urges the development of new treatments. In fact, the ability of P. aeruginosa to form biofilms and to secrete virulence factors like pyocyanine significantly increases its pathogenicity. Hence, the design of non-bactericidal agents that could quench virulence pathways is more and more considered a sustainable therapeutic approach. This so-called ‘anti-virulence’ strategy could provide tools to prevent the selection pressure that triggers the prevalence of resistant strains, potentiate the response of the immune system and restore the efficacy of conventional ATBs against MDR bacteria. A pool of pharmacological targets for the development of anti-virulence agents (AVAs) is the bacterial communication network called Quorum Sensing (QS). In P. aeruginosa, the Pseudomonas Quinolone Signal receptor (PqsR) regulates virulence gene expression in response to cell density or environmental changes when activated by PQS, its natural ligand. This specific QS system plays a predominant role in the production of biofilms that act as protective barriers responsible for a 1,000-fold increase in resistance to ATBs. Therefore, PqsR has emerged as a significant target for the development of QS inhibitors. In the literature, potent QS inhibitors bearing a 4-aminoquinoline scaffold have notably been described. Moreover, our team recently developed a new family of 2-heteroaryl-4-quinolones that successfully inhibits pyocyanin and biofilm production in P. aeruginosa. Based on these studies, we aim at studying novel 2-heteroaryl-4-aminoquinoline analogs as QS quenchers against P. aeruginosa. Our first synthesis works, as well as primary physicochemical and biological assays will be described in the poster.

Novel 2-heteroaryl-4-aminoquinoline agents to quench virulence in multi-drug resistant P. aeruginosa

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ACS Fall 2022

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