New Inhibitors Block Anthrax Toxin

Release Date:
3/7/2005
Contact:
Kirstie Saltsman
saltsmank@nigms.nih.gov

In the fall of 2001, anthrax-contaminated letters sent through the mail caused 11 cases of inhalation anthrax, 5 of which were fatal. This bioterrorist attack focused national attention on the need for new ways to treat the previously uncommon infection, which is caused by the bacterium Bacillus anthracis. Unless antibiotics are administered quickly, they typically fail in treating inhalation anthrax because destroying the bacterium does not neutralize the effects of its three different toxins. One toxin, protective antigen, forms a tunnel through host cell membranes by which the other toxins, edema factor and lethal factor, enter and kill cells. Scientists have found that blocking the passage of lethal factor into cells reduces the severity of anthrax in animals, suggesting that this toxin is a good target for drugs against the disease.

Taking a different approach to foiling lethal factor, Lewis Cantley, Ph.D., of Harvard Medical School has devised a way to prevent the toxin from attacking cellular proteins. Cantley analyzed millions of small proteins to identify chemical inhibitors that latch onto and block the part of lethal factor that would otherwise attach to its targets.

The method worked. Cells in laboratory dishes that were treated with one of the inhibitors survived exposure to lethal factor, while untreated cells died. Cantley then determined the three-dimensional structures of lethal factor attached to several of the inhibitors, which enabled him to observe precisely how the inhibitors bind to the toxin. This information may now be used to design new drugs to combat anthrax.