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New 2-heteroaryl-4-aminoquinolines to tackle Pseudomonas aeruginosa virulence
* 1 , 2 , 3 , * 2
1  Laboratoire AGIR, UR4294, Université de Picardie Jules Verne
2  AGIR, UR 4294, Université de Picardie Jules Verne (UPJV), Amiens, France
3  AGIR, UR 4294, CHU Amiens-Picardie, Amiens, France
Academic Editor: Maria Emília Sousa

https://doi.org/10.3390/ECMC2023-16629 (registering DOI)
Abstract:

The multi-drug resistant pathogen Pseudomonas aeruginosa has been designated by the WHO as a high-priority for the development of new anti-infective treatments. Among Gram-negative bacteria, this species secretes a characteristic cytotoxic pigment called pyocyanin and is able to form biofilms that act as protective barriers against the immune system and antibiotics. Such pathogenicity is mainly regulated by the quorum sensing (QS) pathways that orchestrate the bacterial communication according to the population density. P. aeruginosa possesses a specific QS system : pqs. In this circuit, the transcription factor PqsR stimulates the expression of virulence-related genes via recognition of its auto-inducer PQS (Pseudomonas Quinolone Signal). This notably controls the secretion of pyocyanin and the establishment of biofilms. Therefore, the development of QS inhibitors as anti-virulence agents (AVA) able to tackle P. aeruginosa without affecting bacterial growth appears as a promising strategy to circumvent the selection pressure mediated by conventional antibiotherapy. Ultimately, they could restore the efficacy of antibiotics in dual therapy or potentiate the immune system response in monotherapy. In particular, the design of PqsR inhibitors seems like a sustainable approach to combat P. aeruginosa specifically. In the literature, benzamide-benzimidazole, indole-naphtalene and benzofurane-aminoquinoline hybrids have been reported as such quenchers. Meanwhile, our team discovered a hit 2-heteroaryl-4-quinolone that displays interesting anti-biofilm and anti-pyocyanin activities. By structural analogy with these bi-aromatic molecules, we have recently developed a new family of 2-heteroaryl-4-aminoquinolines with promising anti-virulence properties. The presentation describes the synthesis of our new AVA as well as their physicochemical and biological evaluation.

Keywords: Multi-resistant bacteria; Pseudomonas aeruginosa; Biofilm; Quorum Sensing; anti-virulence agents.

 
 
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