3-Hydroxy-4-tridecanone is the quorum sensing small molecule CAI-1 that controls virulence in Vibrio cholerae

MEDI 14

Douglas A. Higgins1, Megan E. Pomianek, pomianek@princeton.edu2, Christina M. Kraml3, Ronald K. Taylor4, Martin F. Semmelhack, mfshack@princeton.edu2, and Bonnie L. Bassler5. (1) Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, (2) Department of Chemistry, Princeton University, Frick Laboratory, Washington Road, Princeton, NJ 08544, (3) AccelaPure Corporation, 229 Lake Drive, Suite B, Newark, DE 19702, (4) Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH 03755, (5) Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789
Quorum sensing is a process by which groups of bacteria control collective behaviors according to population density. Many of these collective behaviors, including virulence factor production and biofilm formation, play significant roles in the development of infection in human hosts. Such is the case with the bacterium Vibrio cholerae, the causative agent of the disease cholera. To date, the chemical structure of V. cholerae autoinducer-1 (CAI-1) that mediates System 1 quorum sensing in this species has not been identified. In this work, we determine the structure of CAI-1, as isolated from cell supernatants, to be 3-hydroxy-4-tridecanone. We implement a straightforward synthetic strategy to easily access CAI-1 and a variety of structural analogs. Using chemically-synthesized CAI-1, we show that this small molecule initiates quorum sensing behavior in V. cholerae and has a pronounced effect on the formation of the toxin-coregulated pilus crucial to V. cholerae virulence. Our results demonstrate that CAI-1, a small molecule of a novel structural type for bacterial autoinducers, exerts direct control of virulence in V. cholerae through the System 1 quorum sensing circuit.
 

Medicinal Chemistry Award Symposium
1:30 PM-4:20 PM, Sunday, August 19, 2007 BCEC -- 210B, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007