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

Nature volume 450, pages 883–886 (2007)Cite this article

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 (2S,4S)-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.

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Figure 1: Simplified model for quorum sensing in V. cholerae.
Figure 2: Activity, 1 H-NMR spectrum and structural identification of CAI-1 as ( S )-3-hydroxytridecan-4-one.
Figure 3: Activity profiles for synthetic CAI-1 and homologues.
Figure 4: CAI-1 inhibits virulence factor expression.

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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.

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Authors and Affiliations

  1. Department of Molecular Biology,,

    Douglas A. Higgins & Bonnie L. Bassler

  2. Department of Chemistry,,

    Megan E. Pomianek & Martin F. Semmelhack

  3. Lotus Separations LLC, Princeton University, Princeton, New Jersey 08544, USA ,

    Christina M. Kraml

  4. Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA,

    Ronald K. Taylor

  5. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA ,

    Bonnie L. Bassler

Authors
  1. Douglas A. Higgins
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Correspondence to Bonnie L. Bassler.

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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)

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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

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