May 5, 2006

Scientists Design New Anthrax Toxin Inhibitor

graphic of an Anthrax toxin Anthrax toxin forms a structure with a repeating pattern on the surface of cells

Anthrax gained notoriety during the 2001 mail attacks — 22 people became ill and 5 died. The disease is caused by a spore-forming bacterium called Bacillus anthracis that produces a potent toxin. Even with antibiotic therapy, inhalation anthrax, the most severe form of the disease, has a fatality rate of 75%. Scientists funded by NIH's National Institute of Allergy and Infectious Diseases (NIAID), have now engineered a powerful inhibitor of anthrax toxin that worked well in small-scale animal tests.

A critical early step in anthrax toxin formation is the creation of a large structure with a repeating pattern on the surface of cells. This pattern is key to the approach of Dr. Ravi S. Kane of Rensselaer Polytechnic Institute and Dr. Jeremy Mogridge of the University of Toronto, who outline their new technique in the April 23 online edition of the journal Nature Biotechnology. They designed a fatty bubble (called a liposome) studded with thousands of small proteins that can cling tightly to one of components that make up anthrax toxin. When this inhibitor is bound to the toxin structure on the cell surface, it hampers a critical early step in toxin formation.

In test-tube experiments, the liposome inhibitor was 10,000 times more potent than the small proteins themselves. The reason is that the liposome is "polyvalent" — it binds the toxin at multiple sites — and is therefore more potent than an inhibitor that binds only at a single site. The researchers designed the liposome so that the small proteins on its surface are arranged with the same average spacing as the binding sites on the toxin. This allows a firmer bond between the two, making for a much more potent inhibitor.

The investigators tested the anthrax inhibitor in rats as well. When given in relatively small doses, injection of the inhibitor at the same time as anthrax toxin prevented 5 out of 9 rats from becoming ill. Slightly higher doses of the inhibitor prevented 8 out of 9 rats from being sickened by anthrax toxin. Nine additional rats were injected with anthrax toxin only and, of these, 8 became gravely ill. This experiment was the first to demonstrate the efficacy of a liposome-based polyvalent inhibitor in animals, says Dr. Kane.

Using the same technique, the researchers also created a polyvalent inhibitor of cholera toxin that functioned well in test-tube experiments. Dr. Kane says these experiments demonstrate a proof of principle, suggesting that polyvalent inhibitors could be used along with antibiotics in a clinical setting. The researchers next plan to test their inhibitor in animals after infecting them with B. anthracis and allowing the disease process to begin. They'll also try to see how well the inhibitor works along with antibiotic therapy.

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