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Researchers Learn Why

Anthrax Kill - Neutralizing

Protein Sought

From Discovery News Briefs

http://www.discovery.com

5-2-98

Researchers are moving closer to finding drugs to disarm anthrax and make the

deadly bacteria useless as a weapon.

Anthrax is a rapid and highly effective killer. When it infects, the bacteria

produces a toxin, or poison, that attacks cells.

Experts consider anthrax-based biological weapons to be major military

threat. Bioterrorism weapons using anthrax or other bacteria are easier to

make and distribute than nuclear weapons.

" The only treatment now for anthrax is to give massive, massive amounts of

antibiotics, " said S. Duesbery of the cancer institute. " You have to

give it almost immediately after exposure. If you give it 24 hours later, it

is too late. Your patient is dead. "

" An inhibitor drug would make anthrax as a weapon as useful as a water

pistol, " said Dr. F. Vande Woude of the National Cancer Institute and

a co-author of the study.

Anthrax toxin consists of three proteins, and early research showed that one

of the proteins, called lethal factor, or LF, was the major cause of cell

death. But what science didn't know until now is how LF killed the cells.

Vande Woude, Duesbery and their colleagues found that LF disrupts a signaling

system in cells called the MAP-Kinase-Kinase (MAP-K-K) pathway. When this

system is blocked, said Duesbery, a cell " is cut off from the world. " Its

metabolism shuts down and it can no longer divide. The toxin also causes the

massive release of an inflammation protein and destruction of immune system

cells called macrophages.

The result, said Duesbery, is rapid shock and death. In laboratory

experiments, he said, " rats are quite dead within just 40 minutes " when

injected with anthrax toxin.

Now that researchers know the MAP-K-K target of lethal factor, said Duesbery,

" This gives us the first clues of what we need to develop an antitoxin. We

can look at the protein structure of the target and come up with (a protein

molecule) that will block lethal factor from chopping up its target. "

Col. Arthur M. Friedlander, an Army anthrax researcher, said the discovery is

significant in understanding how anthrax kills, but he cautioned that it may

take more than a single antitoxin to disarm the disease.

" It is not just that toxin that kills in this disease, " he said. " But this

offers a new approach that may lead to other inhibitors that would work. "

Ironically, the anthrax cell target was found while NCI researchers were

searching for a way to block the spread of cancer. Vande Woude said the

cell-signaling system that the anthrax toxin turns off is permanently turned

on in some cancers. The goal now is to use lessons learned from the anthrax

research to find a way to selectively shut down the cell signals that promote

cancer, he said.

The research is published in the latest journal Science.