title: Cinnamaldehyde and cinnamaldehyde derivatives reduce virulence in Vibrio spp. by decreasing the DNA-binding activity of the quorum sensing response regulator LuxR.
abstract: BACKGROUND
  To 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  Cinnamaldehyde 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.
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: Tom
authors.initials: T
authors.lastname: Defoirdt
authors.forename: Carol
authors.initials: C
authors.lastname: Miyamoto
authors.forename: Peter
authors.initials: P
authors.lastname: Bossier
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
authors.forename: Hans
authors.initials: H
authors.lastname: Nelis
authors.forename: Tom
authors.initials: T
authors.lastname: Coenye
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001156:Artemia / Q000187:drug effects / Q000382:microbiology / Q000502:physiology; D018441:Biofilms / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D049449:Luminescence; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism; D010860:Pigments, Biological / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014733:Vibrio / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000472:pathogenicity*; D014774:Virulence / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D010860:Pigments, Biological; D012097:Repressor Proteins; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins; D000171:Acrolein; D004247:DNA; D010447:Peptide Hydrolases; C012843:cinnamaldehyde
references.citation: J Dermatol. 2006 Sep;33(9):589-95
references.pmid: 16958802
references.citation: Environ Microbiol. 2001 Nov;3(11):731-6
references.pmid: 11846763
references.citation: J Appl Microbiol. 2007 Jul;103(1):194-203
references.pmid: 17584465
references.citation: J Bacteriol. 2001 Jan;183(2):758-62
references.pmid: 11133972
references.citation: Appl Environ Microbiol. 2007 Jun;73(11):3742-6
references.pmid: 17434996
references.citation: Am Fam Physician. 2007 Aug 15;76(4):539-44
references.pmid: 17853628
references.citation: Biotechnol Bioeng. 2004 Dec 5;88(5):630-42
references.pmid: 15470704
references.citation: J Agric Food Chem. 2000 Nov;48(11):5702-9
references.pmid: 11087542
references.citation: J Microbiol Methods. 2008 Feb;72(2):157-65
references.pmid: 18155789
references.citation: Lett Appl Microbiol. 2006 Aug;43(2):119-24
references.pmid: 16869892
references.citation: Org Lett. 2004 Sep 2;6(18):3043-6
references.pmid: 15330583
references.citation: Mol Microbiol. 1993 Aug;9(4):773-86
references.pmid: 8231809
references.citation: Food Chem Toxicol. 2004 Feb;42(2):157-85
references.pmid: 14667463
references.citation: J Clin Invest. 2003 Nov;112(9):1300-7
references.pmid: 14597754
references.citation: Lett Appl Microbiol. 2006 Nov;43(5):489-94
references.pmid: 17032221
references.citation: J Antimicrob Chemother. 2007 Jul;60(1):49-53
references.pmid: 17491000
references.citation: J Bacteriol. 2005 May;187(9):3214-26
references.pmid: 15838049
references.citation: Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1639-44
references.pmid: 9990077
references.citation: Mol Cell. 2004 Sep 10;15(5):677-87
references.pmid: 15350213
references.citation: Curr Opin Microbiol. 2005 Oct;8(5):534-42
references.pmid: 16111914
references.citation: Nature. 2007 Dec 6;450(7171):883-6
references.pmid: 18004304
references.citation: Int J Med Microbiol. 2006 Apr;296(2-3):61-71
references.pmid: 16487746
references.citation: J Bacteriol. 2002 Mar;184(6):1617-29
references.pmid: 11872713
references.citation: Cell. 2004 Jul 9;118(1):69-82
references.pmid: 15242645
references.citation: Trends Biotechnol. 2007 Oct;25(10):472-9
references.pmid: 17719667
references.citation: J Microbiol Biotechnol. 2007 Feb;17(2):325-34
references.pmid: 18051765
references.citation: Mol Microbiol. 2001 Mar;39(6):1452-63
references.pmid: 11260463
references.citation: J Biol Chem. 1993 Aug 5;268(22):16706-16
references.pmid: 8344950
references.citation: Curr Opin Microbiol. 2003 Apr;6(2):191-7
references.pmid: 12732311
references.citation: J Bacteriol. 1999 Feb;181(3):899-906
references.pmid: 9922254
references.citation: Environ Microbiol. 2005 Aug;7(8):1239-47
references.pmid: 16011761
references.citation: Appl Environ Microbiol. 2006 Sep;72(9):6419-23
references.pmid: 16957276
references.citation: Mol Microbiol. 1999 Jan;31(2):665-77
references.pmid: 10027982
references.citation: Environ Microbiol. 2008 Feb;10(2):328-38
references.pmid: 18028416
references.citation: J Bacteriol. 1997 Jun;179(12):4043-5
references.pmid: 9190823
references.citation: Appl Environ Microbiol. 2004 Dec;70(12):6951-6
references.pmid: 15574886
references.citation: Mol Microbiol. 2002 Mar;43(5):1115-27
references.pmid: 11918800
references.citation: Environ Microbiol. 2007 Oct;9(10):2486-95
references.pmid: 17803774
references.citation: Microbiology (Reading). 2004 May;150(Pt 5):1283-1290
references.pmid: 15133091
references.citation: Mol Microbiol. 1994 May;12(3):403-12
references.pmid: 8065259
references.citation: Microbiology (Reading). 2003 Jul;149(Pt 7):1923-1933
references.pmid: 12855743
references.citation: Appl Environ Microbiol. 2004 Jul;70(7):4193-204
references.pmid: 15240301
references.citation: Food Microbiol. 2007 Sep;24(6):664-70
references.pmid: 17418319