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Molecules 2018, 23(2), 257; https://doi.org/10.3390/molecules23020257

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

1
School of Life Sciences, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK
2
Department of Microbiology, Universidad del Valle and Departamento of Biomedical Sciences, Universidad Santiago de Cali, Cali AA 760035, Colombia
3
Department of Chemistry, Universidad del Valle, Cali AA 25360, Colombia
4
School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK
*
Author to whom correspondence should be addressed.
Received: 22 December 2017 / Revised: 20 January 2018 / Accepted: 20 January 2018 / Published: 28 January 2018
(This article belongs to the Special Issue Design and Synthesis of Quorum-Sensing Inhibitors)
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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. View Full-Text
Keywords: Pseudomonas aeruginosa; PqsR; MvfR; Pseudomonas quinolone signal (PQS); alkylquinolone; quorum sensing inhibition. Pseudomonas aeruginosa; PqsR; MvfR; Pseudomonas quinolone signal (PQS); alkylquinolone; quorum sensing inhibition.
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Soukarieh, F.; Vico Oton, E.; Dubern, J.-F.; Gomes, J.; Halliday, N.; de Pilar Crespo, M.; Ramírez-Prada, J.; Insuasty, B.; Abonia, R.; Quiroga, J.; Heeb, S.; Williams, P.; Stocks, M.J.; Cámara, M. In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa. Molecules 2018, 23, 257.

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