Novel Aminoquinoline Bi-Aromatic Hybrids As Anti-Biofilm Agents Against Pseudomonas Aeruginosa

The antibiotic resistance crisis has led the WHO to name several pathogens as priorities for the development of new treatments. In this context, a promising alternative approach to conventional antibiotics (ATBs) has been explored to fight multi-drug-resistant bacteria. The so-called “anti-virulence strategy” aims at diminishing bacterial pathogenicity without affecting cell growth, in order to circumvent the selection pressure issues mediated by standardantibiotherapy. Anti-virulence agents (AVAs) could find a use in biotherapy to restore the efficacy of ATBs, or in monotherapy to potentiate the immune system’s response. Among the WHO’s targets stands the opportunistic gram-negative bacterium Pseudomonas aeruginosa, the main cause of chronic and hard-to-treat lung infections in immunocompromised patients. A major virulence trait of P. aeruginosa is the development of biofilms, i.e., microcolonies embedded in a protective self-produced extracellular matrix. These complex structures provide advantageous microenvironments for pseudomonal growth, as well as shielding barriers against the immune system and ATBs. The development of biofilms is mostly coordinated by quorum sensing (QS), a bacterial communication network regulating pathogenicity according to population density. Therefore, the development of quorum sensing inhibitors (QSIs) has been considered a good strategy to eradicate P. aeruginosa infections. In the literature, several bi-aromatic hybrids have been described as potent QSIs against P. aeruginosa. By structural analogy, the AGIR laboratory highlighted a first-hit 2-indazolyl-4-quinolone with promising anti-virulence properties. More recently, the team developed a new family of aminoquinoline bi-aromatic hybrids as QSIs able to efficiently inhibit P. aeruginosa motility and biofilm formation. This presentation describes the synthesis of those new AVAs as well as their physicochemical and biological evaluation.