Anti Virulence Factor Project

Background Information

In a recent paper, Hung et al. describes a new strategy for developing anti-microbial drugs. An enzyme required for virulence in cholera was identified, cloned, and tested against a library of small molecules. A compound was found that, while it does not kill the cholera organisms, neutralizes their ability to cause disease. This strategy will be useful in combination therapies for bacterial disease, and for treating viruses, for which there are currently no effective antibiotic equivalents.

Research Problems and Goals

• Identify prevalent organism dependent on a virulence promoter to cause disease.

• Clone relevant regulatory gene into more mass-production friendly organism, such as yeast or bacteria, in order to produce the protein in high enough quantities for mass production.

• Obtain library of small molecule compounds that will serve as potential drugs.

• Develop screening assay for inhibitor potency.

• Perform high-throughput screening on compound library to determine which potential drugs are most active against the protein.

References

• Paper showcasing use of this method in cholera
  • Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization. Hung DT, Shakhnovich EA, Pierson E, Mekalanos JJ Science 2005 Oct 13

• Virulence in malaria
  • Targeting Malaria Virulence and Remodeling Proteins to the Host Erythrocyte Matthias Marti, Robert T. Good, Melanie Rug, Ellen Knuepfer, Alan F. Cowman. Science 10 December 2004: Vol. 306. no. 5703, pp. 1930 - 1933
  • Parasite virulence factors during falciparum malaria: rosetting, cytoadherence, and modulation of cytoadherence by cytokines. P Ringwald, F Peyron, J P Lepers, P Rabarison, C Rakotomalala, M Razanamparany, M Rabodonirina, J Roux, and J Le Bras. Infect Immun. 1993 December; 61(12): 5198–5204.

• Virulence in AIDS
  • Biologic features of HIV-1 that correlate with virulence in the host. Cheng-Mayer C, Seto D, Tateno M, Levy JA. Science. 1988 Apr 1;240(4848):80-2.

• High-throughput screening
  • High-throughput screening: new technology for the 21st century. Robert P Hertzberg, a and Andrew J Pope. Current Opinion in Chemical Biology Volume 4, Issue 4 , 1 August 2000, Pages 445-451