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Scientists Design New Anthrax Toxin Inhibitor
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.
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Anthrax toxin forms a structure with a repeating pattern
on the surface of cells. |
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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