In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in 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 Pseudomonas Quinolone System ( ) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alk...

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Published in:	Molecules (Basel, Switzerland) Vol. 23; no. 2; p. 257
Main Authors:	Soukarieh, Fadi, Vico Oton, Eduard, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J, Cámara, Miguel
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 28-01-2018 MDPI
Subjects:	alkylquinolone Antagonists Anti-Bacterial Agents - chemistry Antibacterial agents Antibiotic resistance Antibiotics Biofilms Cystic fibrosis Docking Drug discovery Inhibitors Molecular Docking Simulation MvfR Nosocomial infection Opportunist infection Pathogens PqsR Pseudomonas aeruginosa Pseudomonas aeruginosa - physiology Pseudomonas quinolone signal (PQS) Public health Pyocyanin Quinolones - metabolism Quorum Sensing - drug effects quorum sensing inhibition Tobramycin Transcription activation Transcription Factors - antagonists & inhibitors Transcription Factors - genetics Transcription Factors - metabolism Virulence Wounds alkylquinolone MvfR Pseudomonas aeruginosa Pseudomonas quinolone signal (PQS) quorum sensing inhibition PqsR
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Summary:	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 Pseudomonas Quinolone System ( ) 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 docking analysis, coupled with screening using a mCTX::P - chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in PAO1-L and PA14 strains. The inhibitor , 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 microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-3049 1420-3049
DOI:	10.3390/molecules23020257