Disulfide Bond-Containing Ajoene Analogues As Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa.

Autor:	Fong J; Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore.; School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore., Yuan M; Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore., Jakobsen TH; Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen , 2200 København N, Denmark., Mortensen KT; Department of Chemistry, Technical University of Denmark , Kemitorvet, 2800 Kgs Lyngby, Denmark., Delos Santos MM; Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore., Chua SL; Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore., Yang L; Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore.; School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore., Tan CH; Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore.; Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University , 21 Nanyang Link, Singapore 637371, Singapore., Nielsen TE; Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore.; Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen , 2200 København N, Denmark., Givskov M; Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore.; Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen , 2200 København N, Denmark.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Jan 12; Vol. 60 (1), pp. 215-227. Date of Electronic Publication: 2016 Dec 28.
DOI:	10.1021/acs.jmedchem.6b01025
Abstrakt:	Since its discovery 22 years ago, the bacterial cell-to-cell communication system, termed quorum sensing (QS), has shown potential as antipathogenic target. Previous studies reported that ajoene from garlic inhibits QS in opportunistic human pathogen Pseudomonas aeruginosa. In this study, screening of an in-house compound library revealed two sulfur-containing compounds which possess structural resemblance with ajoene and inhibit QS in bioreporter assay. Following a quantitative structure-activity relationship (SAR) study, 25 disulfide bond-containing analogues were synthesized and tested for QS inhibition activities. SAR study indicated that the allyl group could be replaced with other substituents, with the most active being benzothiazole derivative (IC 50 = 0.56 μM). The compounds were able to reduce QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin) and successfully inhibit P. aeruginosa infection in murine model of implant-associated infection. Altogether, the QS inhibition activity of the synthesized compounds is encouraging for further exploration of novel analogues in antimicrobial drug development.
Databáze:	MEDLINE
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