title: Cyclo(valine-valine) inhibits Vibrio cholerae virulence gene expression.
abstract: Vibrio cholerae has been shown to produce a cyclic dipeptide, cyclo(phenylalanine-proline) (cFP), that functions to repress virulence factor production. The objective of this study was to determine if heterologous cyclic dipeptides could repress V. cholerae virulence factor production. To that end, three synthetic cyclic dipeptides that differed in their side chains from cFP were assayed for virulence inhibitory activity in V. cholerae. The results revealed that cyclo(valine-valine) (cVV) inhibited virulence factor production by a ToxR-dependent process that resulted in the repression of the virulence regulator aphA. cVV-dependent repression of aphA was found to be independent of known aphA regulatory genes. The results demonstrated that V. cholerae was able to respond to exogenous cyclic dipeptides and implicated the hydrophobic amino acid side chains on both arms of the cyclo dipeptide scaffold as structural requirements for inhibitory activity. The results further suggest that cyclic dipeptides have potential as therapeutics for cholera treatment.
authors.affiliation: University of Pittsburgh School of Medicine, Department of Microbiology and Molecular Genetics, Pittsburgh, PA 15219, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Vikram
authors.affiliation: University of Pittsburgh School of Medicine, Department of Microbiology and Molecular Genetics, Pittsburgh, PA 15219, USA.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Ante
authors.affiliation: University of Pittsburgh School of Medicine, Department of Microbiology and Molecular Genetics, Pittsburgh, PA 15219, USA.
authors.forename: X Renee
authors.initials: XR
authors.lastname: Bina
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: University of Pittsburgh School of Medicine, Department of Microbiology and Molecular Genetics, Pittsburgh, PA 15219, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bina
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014633:Valine / Q000494:pharmacology*; D014734:Vibrio cholerae / Q000187:drug effects*; D037521:Virulence Factors / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D037521:Virulence Factors; D014633:Valine