Anthrax, a disease caused by the spore-forming bacterium Bacillus anthracis, is most deadly when exposure occurs through inhalation. Prompt diagnosis and antibiotic treatment during the early stages of infection are critical. In many cases, however, antibiotics may not be effective--particularly when bacterial overload causes large amounts of anthrax toxin to be released in the body.
Anthrax toxin consists of three proteins: lethal factor, protective antigen, and edema factor, all of which work in concert to kill host cells. While the exact mechanism of anthrax toxin is not yet well understood, it is clear that developing methods to inhibit toxin assembly and/or function is critically important.
In an article published in this month's issue of Nature Structural and Molecular Biology, investigators from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), the National Cancer Institute (NCI), the Burnham Institute, and the Harvard Institutes of Medicine report using a high-throughput assay to screen a group of 1,990 compounds known as the NCI diversity set. The molecular properties of this group are predictive of a larger set of more than 100,000 compounds.
Using a two-stage screening assay, the team identified a number of compounds that inhibited the activity of LF. All inhibitors were further verified by high-performance liquid chromatography and their efficacy was validated in cell culture. Finally, molecular modeling techniques were used to predict structural features that contribute to inhibitor binding and potency.
These techniques revealed a common pharmacophore--a "scaffold" upon which future therapeutics can be built. This pharmacophore will serve as a basis for directing future effo
Contact: Caree Vander Linden
US Army Medical Research Institute of Infectious Diseases