Small molecule probes of the receptor binding site in the Vibrio cholerae CAI-1 quorum sensing circuit

Megan E. Bolitho, Lark J. Perez, Matthew J. Koch, Wai Leung Ng, Bonnie Lynn Bassler, Martin F. Semmelhack

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Based on modification of separate structural features of the Vibrio cholerae quorum sensing signal, (S)-3-hydroxytridecan-4-one (CAI-1), three focused compound libraries have been synthesized and evaluated for biological activity. Modifications to the acyl tail and α-hydroxy ketone typically provided agonists with activities correlated to tail length and conservative changes to the hydroxy ketone. Among the molecules identified within this collection of agonists is Am-CAI-1 (B11), which is among the most potent agonists reported to date with an EC 50 of 0.21 μM. Modifications to the ethyl side chain delivered molecules with both agonist and antagonist activity, including m-OH-Ph-CAI-1 (C13) which is the most potent antagonist reported to date with an IC 50 of 36 μM. The molecules described in this manuscript are anticipated to serve as valuable tools in the study of quorum sensing in Vibrio cholerae and provide new leads in the development of an antivirulence therapy against this human pathogen.

Original languageEnglish (US)
Pages (from-to)6906-6918
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number22
DOIs
StatePublished - Nov 15 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Keywords

  • Agonist
  • Antagonist
  • Autoinducer
  • Quorum sensing
  • Structure-activity relationship
  • Vibrio cholerae

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