DOI: 10.1126/science.1116739. Small-Molecule Inhibitor of <i>Vibrio cholerae</i> Virulence and Intestinal Colonization

Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization

10.1126/science.1116739

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

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 .

Bibliography

Hung, D. T., Shakhnovich, E. A., Pierson, E., & Mekalanos, J. J. (2005). Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization. Science, 310(5748), 670â674.

Authors 4

Deborah T. Hung (first)
Elizabeth A. Shakhnovich (additional)
Emily Pierson (additional)
John J. Mekalanos (additional)

References 24 Referenced 297

10.1126/science.1106753
M. K. Waldor, J. J. Mekalanos, in Enteric Infections and Immunity, L. J. Paradise, Ed. (Plenum, New York, 1996), pp. 37–55. / Enteric Infections and Immunity (1996)
Materials and methods are available as supporting material on Science Online.
10.1126/science.272.5270.1910
10.1111/j.1365-2958.1992.tb01489.x
10.1128/jb.174.21.6974-6980.1992
10.1111/j.1365-2958.1995.tb02408.x
10.1073/pnas.2628026100
10.1046/j.1365-2958.2000.02111.x
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.
10.1006/plas.1997.1294
10.1046/j.1365-2958.1997.2191585.x
Strain S533 was obtained from the Mekalanos lab collection of V. cholerae strain originally isolated in 1981 from Soongnern Hospital in Thailand.
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.
10.1128/IAI.67.8.3733-3739.1999
10.1073/pnas.84.9.2833
10.1128/AAC.33.9.1447
10.1016/S0092-8674(00)81551-2
10.1073/pnas.90.3.965
10.1073/pnas.0407661102
10.1093/emboj/cdg366
10.1016/S1074-5521(03)00046-2
10.1038/nsmb708
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.).

Dates

Type	When
Created	19 years, 10 months ago (Oct. 13, 2005, 8:43 p.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 8:53 p.m.)
Indexed	4 months, 2 weeks ago (April 10, 2025, 7:29 a.m.)
Issued	19 years, 10 months ago (Oct. 28, 2005)
Published	19 years, 10 months ago (Oct. 28, 2005)
Published Print	19 years, 10 months ago (Oct. 28, 2005)

Funders 0

None

BibTeX

@article{Hung_2005, title={Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization}, volume={310}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1116739}, DOI={10.1126/science.1116739}, number={5748}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Hung, Deborah T. and Shakhnovich, Elizabeth A. and Pierson, Emily and Mekalanos, John J.}, year={2005}, month=oct, pages={670–674} }

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