title: A quorum sensing-disrupting brominated thiophenone with a promising therapeutic potential to treat luminescent vibriosis.
abstract: Vibrio harveyi is amongst the most important bacterial pathogens in aquaculture. Novel methods to control this pathogen are needed since many strains have acquired resistance to antibiotics. We previously showed that quorum sensing-disrupting furanones are able to protect brine shrimp larvae against vibriosis. However, a major problem of these compounds is that they are toxic toward higher organisms and therefore, they are not safe to be used in aquaculture. The synthesis of brominated thiophenones, sulphur analogues of the quorum sensing-disrupting furanones, has recently been reported. In the present study, we report that these compounds block quorum sensing in V. harveyi at concentrations in the low micromolar range. Bioluminescence experiments with V. harveyi quorum sensing mutants and a fluorescence anisotropy assay indicated that the compounds disrupt quorum sensing in this bacterium by decreasing the ability of the quorum sensing master regulator LuxR to bind to its target promoter DNA. In vivo challenge tests with gnotobiotic brine shrimp larvae showed that thiophenone compound TF310, (Z)-4-((5-(bromomethylene)-2-oxo-2,5-dihydrothiophen-3-yl)methoxy)-4-oxobutanoic acid, completely protected the larvae from V. harveyi BB120 when dosed to the culture water at 2.5 µM or more, whereas severe toxicity was only observed at 250 µM. This makes TF310 showing the highest therapeutic index of all quorum sensing-disrupting compounds tested thus far in our brine shrimp model system.
authors: Laboratory of Aquaculture & Artemia Reference Center, Ghent University, Ghent, Belgium. Tom.Defoirdt@UGent.be
authors: Tom
authors: T
authors: Defoirdt
authors: Tore
authors: T
authors: Benneche
authors: Gilles
authors: G
authors: Brackman
authors: Tom
authors: T
authors: Coenye
authors: Patrick
authors: P
authors: Sorgeloos
authors: Anne Aamdal
authors: AA
authors: Scheie
mesh_terms: D000818:Animals; D001156:Artemia / Q000382:microbiology; D004269:DNA, Bacterial / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000382:microbiology; D008163:Luminescent Measurements; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D053038:Quorum Sensing / Q000187:drug effects*; D012097:Repressor Proteins / Q000378:metabolism; D013386:Succinates / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism; D014733:Vibrio / Q000166:cytology* / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014735:Vibrio Infections / Q000517:prevention & control*
chemical_list: C579540:4-((5-(bromomethylene)-2-oxo-2,5-dihydrothiophen-3-yl)methoxy)-4-oxobutanoic acid; D004269:DNA, Bacterial; D012097:Repressor Proteins; D013386:Succinates; D013876:Thiophenes; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins