posted on 2024-01-03, 15:35authored byFadi Soukarieh, Alaa Mashabi, William Richardson, Eduard Vico Oton, Manuel Romero, Jean-Frédéric Dubern, Shaun N. Robertson, Simone Lucanto, Zoe Markham-Lee, Tomás Sou, Irena Kukavica-Ibrulj, Roger C. Levesque, Christel A. S. Bergstrom, Nigel Halliday, Barrie Kellam, Jonas Emsley, Stephan Heeb, Paul Williams, Michael J. Stocks, Miguel Cámara
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 PpqsA-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.