Pseudomonas aeruginosa is one of the top priority pathogens that requires immediate attention according to the World Health Organisation (WHO). Due to the alarming shortage of novel antimicrobials, targeting quorum sensing (QS), a bacterial cell to cell signaling system controlling virulence, has emerged as a promising approach as an antibiotic adjuvant therapy. Interference with the pqs system, one of three QS systems in P. aeruginosa, results in reduction of bacterial virulence gene expression and biofilm maturation. Herein, we report a hit to lead process to fine-tune the potency of our previously reported inhibitor 1 (IC₅₀ 3.2 μM in P. aeruginosa PAO1-L), which led to the discovery of 2-(4-(3-((6-chloro-1-isopropyl-1H-benzo[d]imidazol-2-yl)amino)-2-hydroxypropoxy)phenyl)acetonitrile (6f) as a potent PqsR antagonist. Compound 6f inhibited the PqsR-controlled P_pqsA-lux transcriptional reporter fusion in P. aeruginosa at low submicromolar concentrations. Moreover, 6f showed improved efficacy against P. aeruginosa CF isolates with significant inhibition of pyocyanin, 2-alkyl-4(1H)-quinolones production.

中文翻译：

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新型 1H-苯并[d]咪唑基 PqsR 抑制剂作为铜绿假单胞菌感染辅助治疗的设计、合成和评估

根据世界卫生组织 (WHO) 的说法，铜绿假单胞菌是需要立即关注的首要病原体之一。由于新型抗菌药物的严重短缺，针对群体感应（QS）（一种控制毒力的细菌细胞间信号系统）已成为一种有前景的抗生素辅助治疗方法。pqs系统（铜绿假单胞菌的三个 QS 系统之一）的干扰会导致细菌毒力基因表达和生物膜成熟的减少。在此，我们报告了一个先导过程，以微调我们之前报道的抑制剂1的效力（铜绿假单胞菌PAO1-L 中的 IC ₅₀ 3.2 μM ），这导致了 2-(4-(3-( (6-氯-1-异丙基-1 H-苯并[ d ]咪唑-2-基)氨基)-2-羟基丙氧基)苯基)乙腈( 6f )作为有效的PqsR拮抗剂。化合物6f在低亚微摩尔浓度下抑制铜绿假单胞菌中PqsR 控制的 P _pqsA - lux转录报告基因融合。此外，6f对铜绿假单胞菌CF 分离株表现出更高的功效，并显着抑制绿脓菌素、2-烷基-4(1 H )-喹诺酮类药物的产生。