The major vibrio cholerae autoinducer and its role in virulence factor production

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The major vibrio cholerae autoinducer and its role in virulence factor production"


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ABSTRACT _Vibrio cholerae_, the causative agent of the human disease cholera, uses cell-to-cell communication to control pathogenicity and biofilm formation1,2. This process, known as quorum


sensing, relies on the secretion and detection of signalling molecules called autoinducers. At low cell density _V. cholerae_ activates the expression of virulence factors and forms


biofilms. At high cell density the accumulation of two quorum-sensing autoinducers represses these traits. These two autoinducers, cholerae autoinducer-1 (CAI-1) and autoinducer-2 (AI-2),


function synergistically to control gene regulation, although CAI-1 is the stronger of the two signals. _V. cholerae_ AI-2 is the furanosyl borate diester


(2_S_,4_S_)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran borate3. Here we describe the purification of CAI-1 and identify the molecule as (_S_)-3-hydroxytridecan-4-one, a new type of


bacterial autoinducer. We provide a synthetic route to both the _R_ and _S_ isomers of CAI-1 as well as simple homologues, and we evaluate their relative activities. Synthetic


(_S_)-3-hydroxytridecan-4-one functions as effectively as natural CAI-1 in repressing production of the canonical virulence factor TCP (toxin co-regulated pilus). These findings suggest that


CAI-1 could be used as a therapy to prevent cholera infection and, furthermore, that strategies to manipulate bacterial quorum sensing hold promise in the clinical arena. Access through


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104, 11145–11149 (2007) Article  ADS  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS We thank members of the Bassler, Semmelhack and Hughson groups for


discussions. We thank I. Pelczer for the double-quantum filtered correlation spectroscopy experiment and initial 13C-NMR studies. This work was supported by the Howard Hughes Medical


Institute (B.L.B.) and grants from the National Science Foundation (B.L.B.) and the National Institutes of Health (B.L.B. and M.F.S.). M.E.P. was supported by a graduate fellowship from


Amgen through the Medicinal Chemistry Division of the American Chemical Society and by the Horst Witzel Prize from the Cephalon Corporation. AUTHOR CONTRIBUTIONS D.A.H. purified CAI-1 and


performed biological activity and virulence assays. M.E.P. performed chemical analyses and prepared synthetic CAI-1. C.M.K. aided in CAI-1 purification and conducted chiral chromatographic


analyses. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular Biology,, Douglas A. Higgins & Bonnie L. Bassler * Department of Chemistry,, Megan E. Pomianek & 


Martin F. Semmelhack * Lotus Separations LLC, Princeton University, Princeton, New Jersey 08544, USA , Christina M. Kraml * Department of Microbiology and Immunology, Dartmouth Medical


School, Hanover, New Hampshire 03755, USA, Ronald K. Taylor * Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA , Bonnie L. Bassler Authors * Douglas A. Higgins View author


publications You can also search for this author inPubMed Google Scholar * Megan E. Pomianek View author publications You can also search for this author inPubMed Google Scholar * Christina


M. Kraml View author publications You can also search for this author inPubMed Google Scholar * Ronald K. Taylor View author publications You can also search for this author inPubMed Google


Scholar * Martin F. Semmelhack View author publications You can also search for this author inPubMed Google Scholar * Bonnie L. Bassler View author publications You can also search for this


author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Bonnie L. Bassler. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests.


SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains the scheme for synthesis of CAI-1 and homologues (Supplementary Scheme 1), GC/MS data for extracts and synthetic


materials (Supplementary Figs. 1-3), chiral SFC traces (Supplementary Figure 4), representative signalling molecules (Supplementary Figure 5), analysis of CAI-1 stability (Supplementary


Figure 6), Supplementary Methods, Supplementary Notes containing references used in synthesis, and Supplementary NMR spectra of extracted autoinducer, synthetic autoinducer, and homologues.


(PDF 8603 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Higgins, D., Pomianek, M., Kraml, C. _et al._ The major _Vibrio cholerae_ autoinducer and


its role in virulence factor production. _Nature_ 450, 883–886 (2007). https://doi.org/10.1038/nature06284 Download citation * Received: 12 August 2007 * Accepted: 19 September 2007 *


Published: 14 November 2007 * Issue Date: 06 December 2007 * DOI: https://doi.org/10.1038/nature06284 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this


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