Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization.
Increasing antibiotic resistance requires the development of new approaches to combating infection. Virulence gene expression in vivo represents a target for antibiotic discovery that has not yet been explored. A high-throughput, phenotypic screen was used to identify a small molecule 4-[N-(1,8-naphthalimide)]-n-butyric acid, virstatin, that inhibits virulence regulation in Vibrio cholerae. By inhibiting the transcriptional regulator ToxT, virstatin prevents expression of two critical V. cholerae virulence factors, cholera toxin and the toxin coregulated pilus. Orogastric administration of virstatin protects infant mice from intestinal colonization by V. cholerae.
Hung
Deborah T
DT
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. dhung@partners.org
Shakhnovich
Elizabeth A
EA
Pierson
Emily
E
Mekalanos
John J
JJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D002460:Cell Line; D002771:Cholera / Q000382:microbiology; D002772:Cholera Toxin / Q000096:biosynthesis; D010861:Fimbriae, Bacterial / Q000187:drug effects; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D007421:Intestine, Small / Q000382:microbiology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009281:Naphthalenes / Q000494:pharmacology*; D053644:Naphthalimides; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects; D014734:Vibrio cholerae / Q000187:drug effects* / Q000472:pathogenicity; D014774:Virulence / Q000187:drug effects; D037521:Virulence Factors / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002087:Butyrates; D009281:Naphthalenes; D053644:Naphthalimides; D014157:Transcription Factors; D037521:Virulence Factors; C505381:virstatin; C075626:tcpN protein, Vibrio cholerae; D002772:Cholera Toxin