title: Synthesis and evaluation of thiazolidinedione and dioxazaborocane analogues as inhibitors of AI-2 quorum sensing in Vibrio harveyi.
abstract: Two focused libraries based on two types of compounds, that is, thiazolidinediones and dioxazaborocanes were designed. Structural resemblances can be found between thiazolidinediones and well-known furanone type quorum sensing (QS) inhibitors such as N-acylaminofuranones, and/or acyl-homoserine lactone signaling molecules, while dioxazaborocanes structurally resemble previously reported oxazaborolidine derivatives which antagonized autoinducer 2 (AI-2) binding to its receptor. Because of this, we hypothesized that these compounds could affect AI-2 QS in Vibrio harveyi. Although all compounds blocked QS, the thiazolidinediones were the most active AI-2 QS inhibitors, with EC(50) values in the low micromolar range. Their mechanism of inhibition was elucidated by measuring the effect on bioluminescence in a series of V. harveyi QS mutants and by DNA-binding assays with purified LuxR protein. The active compounds neither affected bioluminescence as such nor the production of AI-2. Instead, our results indicate that the thiazolidinediones blocked AI-2 QS in V. harveyi by decreasing the DNA-binding ability of LuxR. In addition, several dioxazaborocanes were found to block AI-2 QS by targeting LuxPQ.
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium. Gilles.brackman@UGent.be
authors.forename: Gilles
authors.initials: G
authors.lastname: Brackman
authors.forename: Abed Al Aziz
authors.initials: AA
authors.lastname: Al Quntar
authors.forename: Claes D
authors.initials: CD
authors.lastname: Enk
authors.forename: Izet
authors.initials: I
authors.lastname: Karalic
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Nelis
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
authors.forename: Morris
authors.initials: M
authors.lastname: Srebnik
authors.forename: Tom
authors.initials: T
authors.lastname: Coenye
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D053038:Quorum Sensing / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014733:Vibrio / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione