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


Eduard Vico Oton

Janice Gomes

Nigel Halliday

Maria de Pilar Crespo


Braulio Insuasty

Rodrigo Abonia

Jairo Quiroga

Professor of Molecular Microbiology

Professor of Medicinal Chemistry and Drug Discovery

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Professor of Molecular Microbiology


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 biofilmformation 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.


Soukarieh, F., Vico Oton, E., Dubern, J., Gomes, J., Halliday, N., de Pilar Crespo, M., …Cámara, M. (2018). In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa. Molecules, 23(2), 1-15.

Journal Article Type Article
Acceptance Date Jan 20, 2018
Online Publication Date Jan 28, 2018
Publication Date Jan 28, 2018
Deposit Date Jan 29, 2018
Publicly Available Date Jan 29, 2018
Journal Molecules
Electronic ISSN 1420-3049
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 23
Issue 2
Article Number 257
Pages 1-15
Keywords Pseudomonas aeruginosa; PqsR; MvfR; Pseudomonas quinolone signal (PQS); alkylquinolone; quorum sensing inhibition
Public URL
Publisher URL


molecules-23-00257.pdf (2.3 Mb)

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