title: Disulfide Bond-Containing Ajoene Analogues As Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa.
abstract: 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 (IC50= 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.
authors.affiliation: 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.
authors.forename: July
authors.initials: J
authors.lastname: Fong
authors.affiliation: Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen , 2200 København N, Denmark.
authors.forename: Tim Holm
authors.initials: TH
authors.lastname: Jakobsen
authors.affiliation: Department of Chemistry, Technical University of Denmark , Kemitorvet, 2800 Kgs Lyngby, Denmark.
authors.forename: Kim T
authors.initials: KT
authors.lastname: Mortensen
authors.affiliation: Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: May Margarette Salido
authors.initials: MM
authors.lastname: Delos Santos
authors.affiliation: Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University , 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Song Lin
authors.initials: SL
authors.lastname: Chua
authors.affiliation: 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.
authors.forename: Liang
authors.identifier: 0000-0002-9225-1995
authors.initials: L
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Choon Hong
authors.initials: CH
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nielsen
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004220:Disulfides / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D053038:Quorum Sensing / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013454:Sulfoxides; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D004220:Disulfides; D013454:Sulfoxides; C048980:ajoene