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New study identifies inhibitor of anthrax toxin
Findings could lead to more effective therapy for deadly agent
A research team led by scientists at Beth Israel Deaconess Medical Center (BIDMC)
and Harvard Medical School (HMS) has identified a group of small molecules that
inhibit a deadly toxin associated with inhalational anthrax. Described in the
January 2004 issue of Nature Structural & Molecular Biology, these findings
could eventually lead to the development of a protease inhibitor drug, which in
combination with antibiotics could be used to treat anthrax cases later in the
disease, at a point when antibiotics alone are no longer effective.
"Unlike most types of bacteria, Bacillus anthracis has the
ability to produce large amounts of a toxin that can kill the patient even after
antibiotics have destroyed the bacteria," explains the study's senior
author Lewis Cantley, Ph.D., Chief of the Division of Signal Transduction at
BIDMC and Professor of Systems Biology at HMS. "This toxin is released
within days of the initial infection, and is impervious to antibiotics."
Because the initial symptoms of the disease - fever, cough and chest pain -
mimic colds and flu, early diagnosis is extremely difficult; as a result, some
90 percent of all cases of inhalational anthrax prove fatal.
"Toxins act in two ways," adds BIDMC scientist and first author
Benjamin Turk, Ph.D. "First, they cripple the cells that fight bacterial
infection, thereby enabling the spread of bacteria early in the disease. Later
in the process," he adds, "they contribute to the death of macrophage
cells, leading to the shutdown of the body's immune system." In fact,
autopsies of patients who have died from inhalational anthrax reveal that the
high doses of antibiotics have killed the bacteria, indicating that the patients
have died from the toxins rather than a persistent infection.
Using a "mixture-based peptide library" technique developed by
Turk, the researchers analyzed trillions of peptides to determine an optimal
peptide substrate for lethal factor, the active agent in the anthrax toxin.
Based on the structure of the optimal substrate, small molecule inhibitors were
identified. Finally, crystal structures of lethal factor protease bound to its
optimal substrate and to small molecule inhibitors revealed new approaches to
enable the design of better inhibitors that might prove effective for clinical
use.
The mechanism by which anthrax lethal factor kills human cells is not yet
clear. The protease activity of this toxin is known to attack a family of
protein kinases called map kinase kinases (MEKKs), which mediate many cellular
responses, including cytokine release and cell survival. The availability of
drug inhibitors may facilitate the understanding of the effect of lethal factor
on these pathways. Protease inhibitor drugs have gained popularity in recent
years, notably in the treatment of HIV infections. They work by disabling native
protease enzymes and like a key fitting perfectly into a lock, "lock
up" the enzyme, rendering it ineffectual
"There could be a number of advantages to taking this approach in
attacking inhalational anthrax," notes Cantley. "Unlike an anti-serum,
which would require that whole populations be vaccinated -- regardless of
whether or not an anthrax outbreak developed -- a therapeutic combination of
antibiotics and protease inhibitor drugs wouldn't have to be used except in the
incidence of actual disease. This approach would not only reduce the risk of
side effects, but could also prove cost effective."
Study coauthors include Robert Liddington, Ph.D., Thiang Yian Wong, Ph.D.,
and Robert Schwarzenbacher, Ph.D., of The Burnham Institute, La Jolla,
California; R. John Collier, Ph.D., of the Department of Microbiology and
Molecular Genetics, Harvard Medical School; and Emily Jarrell of BIDMC.
- BIDMC
More information:
Bonnie Prescott, 617-667-7306; bprescot@bidmc.harvard.edu
John Lacey, 617-432-0442; public_affairs@hms.harvard.edu
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