Abstract
BackgroundTo date, only few compounds targeting the AI-2 based quorum sensing (QS) system are known. In the present study, we screened cinnamaldehyde and substituted cinnamaldehydes for their ability to interfere with AI-2 based QS. The mechanism of QS inhibition was elucidated by measuring the effect on bioluminescence in several Vibrio harveyi mutants. We also studied in vitro the ability of these compounds to interfere with biofilm formation, stress response and virulence of Vibrio spp. The compounds were also evaluated in an in vivo assay measuring the reduction of Vibrio harveyi virulence towards Artemia shrimp.ResultsOur results indicate that cinnamaldehyde and several substituted derivatives interfere with AI-2 based QS without inhibiting bacterial growth. The active compounds neither interfered with the bioluminescence system as such, nor with the production of AI-2. Study of the effect in various mutants suggested that the target protein is LuxR. Mobility shift assays revealed a decreased DNA-binding ability of LuxR. The compounds were further shown to (i) inhibit biofilm formation in several Vibrio spp., (ii) result in a reduced ability to survive starvation and antibiotic treatment, (iii) reduce pigment and protease production in Vibrio anguillarum and (iv) protect gnotobiotic Artemia shrimp against virulent Vibrio harveyi BB120.ConclusionCinnamaldehyde and cinnamaldehyde derivatives interfere with AI-2 based QS in various Vibrio spp. by decreasing the DNA-binding ability of LuxR. The use of these compounds resulted in several marked phenotypic changes, including reduced virulence and increased susceptibility to stress. Since inhibitors of AI-2 based quorum sensing are rare, and considering the role of AI-2 in several processes these compounds may be useful leads towards antipathogenic drugs.
Highlights
To date, only few compounds targeting the AI-2 based quorum sensing (QS) system are known
Cinnamaldehyde and cinnamaldehyde derivatives interfere with AI-2 based QS in various Vibrio spp. by decreasing the DNA-binding ability of LuxR
The bioluminescence was not inhibited by cinnamaldehyde and cinnamaldehyde derivatives and these results indicate that the enzymes of Vibrio harveyi involved in bioluminescence are not inhibited by cinnamaldehyde or cinnamaldehyde derivatives
Summary
Only few compounds targeting the AI-2 based quorum sensing (QS) system are known. AI-2 based QS was found to play an important role in regulating the production of several virulence factors, biofilm formation and stress responses in several Vibrio spp. In Vibrio cholerae, CAI-1 was found to be the principle signal molecule in virulence regulation [8] Because of this involvement in virulence, inhibitors of AI-2 based QS have been proposed as novel antipathogenic agents. Halogenated furanones have previously been shown to disrupt AHL and AI-2 based quorum sensing in Vibrio spp. by decreasing the DNA-binding activity of the response regulator LuxR [24,25,26]. The goal of the present study was to determine the mechanism of action of cinnamaldehyde and to evaluate its effect on virulence of Vibrio spp. in vitro and in vivo
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