March 5, 2007

Compounds Show Promise Against Potential Bioterror Agent

Clostridium botulinum bacteria up close. Clostridium botulinum bacteria up close. CDC

Botulism is a rare but serious illness that causes paralysis and can be fatal.It's caused by nerve toxins made by the bacterium Clostridium botulinum. "Type A" toxin is so deadly and easy to produce that the U.S. Centers for Disease Control and Prevention (CDC) considers it one of the highest-risk agents for bioterrorism. In a new study, researchers have identified two small molecules that could prove to be ideal countermeasures for a bioterror attack using botulinum toxin A.

C. botulinum bacteria, which are commonly found in soil, can form spores that allow them to survive in a dormant state until they're exposed to conditions that support their growth. Infant botulism, the most common type of botulism, occurs when infants consume these spores, which then grow in their intestines and release toxin. In adults, most outbreaks are caused by contaminated home-canned foods. You can also get botulism through contaminated wounds.

If diagnosed early, botulism can be treated with an antitoxin, which blocks the action of the toxin in the blood. But recovery still takes many months. The antitoxin can also cause serious side effects, has only a very short window of application and is expensive to produce in large enough quantities to combat a bioterrorism attack. Dr. Kim Janda of The Scripps Research Institute and his colleagues, with funding from NIH's National Institute of Allergy and Infectious Diseases (NIAID) and The Skaggs Institute for Chemical Biology, set out to find other compounds that could act against botulinum toxin A.

The deadly toxin is known to attack a protein called SNAP-25 that is involved in nerve cell communication. The researchers therefore screened a "library" of about 66,000 small molecules to find ones that could disrupt the molecular interaction between the toxin and SNAP-25. Their study was published in the February 20, 2007, issue of the Proceedings of the National Academy of Sciences.

The researchers found seven compounds they decided to test further in living animals. They also added an eighth compound the group had previously developed, called 2,4-dichlorocinnamic hydroxamic acid, that has a completely different mode of action. Mice were given botulinum toxin A along with injections of the potential inhibitors.

Two of the compounds — 2,4-dichlorocinnamic hydroxamic acid and one of the small molecules, NA-A1B2C10 — modestly extended the animals' lives without noticeable side effects. Interestingly, NA-A1B2C10 had been the least effective of the final compounds at protecting SNAP-25 in the laboratory, demonstrating the importance of testing such compounds in living systems.

These small molecules show promise against botulinum toxin A in animal models, but more studies are needed to demonstrate their efficacy. Both have relatively simple structures, so their biological activity might be readily optimized. The two compounds also have different modes of action, so they may be able to complement each other in a "cocktail" therapy.

— by Harrison Wein, Ph.D.

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