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.
Highlights
Antimicrobial resistance has emerged as a global threat to public health, driven by complex resistance mechanisms, a lack of new antibiotics and the misuse of clinically approved antibacterial agents [1,2]
Despite some reports on the emergence of resistance to these agents, these approaches are becoming more popular for treating bacterial infections, as they pose less selective pressure on the bacterial pathogen [37,38]
Disruption of quorum sensing (QS) can provide an alternative approach to conventional antibacterial therapy, as it targets bacterial virulence, rather than bacterial viability [4,39,40,41]
Summary
Antimicrobial resistance has emerged as a global threat to public health, driven by complex resistance mechanisms, a lack of new antibiotics and the misuse of clinically approved antibacterial agents [1,2]. A novel approach to combat antimicrobial resistance has begun to attract attention, based on disarming bacterial virulence through the disruption of bacterial quorum sensing (QS)-mediated communication systems. 2 of resistant antibiotics is Pseudomonas aeruginosa, an opportunistic gram-negative pathogen and leading cause of attention, based on disarming bacterial virulence through the disruption of bacterial quorum sensing diverse nosocomial infections, mainly in immunocompromised patients and individuals with cystic (QS)-mediated communication systems. QS employs diffusible signals, sometimes called fibrosis [7,8]
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