In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilm formation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.

Virtual Screening and Biomolecular Interactions of CviR-Based Quorum Sensing Inhibitors Against Chromobacterium violaceum

“…Due to misuse and overuse of antibiotics along with complex bacterial drug resistance mechanisms, antimicrobial resistance has emerged as a global threat (Soukarieh et al, 2018 ). According to WHO's Global Antimicrobial Surveillance System (GLASS), occurrence of MDR infections was found among half a million people all around the world.…”

“…Recently, disarming the bacterial virulence seems to be a potential alternate strategy to combat MDR (Rangel-Vega et al, 2015 ; Mookherjee et al, 2018 ). AHL mediated quorum sensing inhibition was reported to be effective in many pathogens including C.violaceum, Pseudomonas aeruginosa (Kim et al, 2015 ; Deryabin and Inchagova, 2018 ; Pérez-López et al, 2018 ; Soukarieh et al, 2018 ; Zhou et al, 2018 ). Since, natural products are the alluring sources of drug discovery, we intended to screen the CviR inhibitors from phytochemicals.…”

Dual bioresponsive antibiotic and quorum sensing inhibitor combination nanoparticles for treatment of Pseudomonas aeruginosa biofilms in vitro and ex vivo

“…Although ACNQ has a micromolar IC 50 , more potent PqsR analogues with nanomolar efficacies have recently been described and may offer improved potency as antibiotic adjuvants when delivered in NPs. 23,41 Alternatively, a more rapid route to clinical testing could be achieved by incorporating re-purposed FDA-approved drugs such as clofoctol, an compound that acts as an antibiotic against Gram-positive but not Gram-negative bacteria but is a potent PqsR antagonist for P. aeruginosa. 42 For the delivery system we selected alginate as the carrier polymer, in part because alginate oligomers have previously been shown to inhibit biofilm formation and potentiate the action of antibiotics against P. aeruginosa.…”

Quorum‐sensing system in Acinetobacter baumannii : a potential target for new drug development

“…The QS system in P. aeruginosa is called pqs which regulates virulence and biofilm development, via the transcriptional regulator, PqsR. Four potent 4‐amino‐quinoline‐based compounds (Ia, Ii, Ia, Ii) were assessed to bind to PqsR and act as PqsR antagonists resulting in the inhibition of pqs signalling which ultimately disrupt biofilm and its sensitivity to antibiotics (Soukarieh et al ).…”