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Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization

Science
28 Oct 2005
Vol 310, Issue 5748
pp. 670-674

Abstract

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.

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File (hung-som.pdf)

References and Notes

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DTH3060 is derived from E. coli strain VJ787 (put::ctx-lacZ) by deletion of tolC, an outer membrane porin, to confer greater sensitivity to virstatin.
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CI represents the ratio of test strain to wild type recovered from the intestine (or after overnight in vitro growth) divided by the ratio of input test strain to wild type. C6706 was marked with a lacZ mutation that does not affect colonization but allows it to be distinguished from S533 colonies by blue/white detection on LB-agar plates with Xgal. When the number of bacteria recovered were below the detection limit, 1 was chosen as the denominator to calculate the CI.
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We thank the National Cancer Institute's Initiative for Chemical Genetics (S. L. Schreiber, P.I.) and the Harvard Institute of Chemistry and Cell Biology for their support of and assistance with the high-throughput small molecule screen; the New England Regional Center of Excellence in Biodefense and Infectious Disease Research for its continued support of research activities involving the identification of small molecule inhibitors of bacterial virulence; and S. Chiang, J. Mougous, and J. Zhu for review of the manuscript. Supported by NIH grant nos. K08 AI060708-01 (D.T.H.) and AI26289 (J.J.M.) and by an NSF predoctoral fellowship (E.A.S.).

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Published In

Science
Volume 310 | Issue 5748
28 October 2005

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Submission history

Received: 29 June 2005
Accepted: 22 September 2005
Published in print: 28 October 2005

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Notes

Supporting Online Material
www.sciencemag.org/cgi/content/full/1116739/DC1
Materials and Methods
SOM Text
Tables S1 to S3
References and Notes

Authors

Affiliations

Deborah T. Hung* [email protected]
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Elizabeth A. Shakhnovich
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Emily Pierson
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
John J. Mekalanos
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Notes

*
To whom correspondence should be addressed. E-mail: [email protected]

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