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Researchers Identify Structure of Lethal Anthrax Molecule - 2002-01-24

U.S. scientists have identified the structure of the third anthrax molecule that causes the bacterium to be deadly. The shapes of the two other molecules that make it toxic have already been described. The new work offers yet another target for potential drugs to block anthrax and thwart its use as a biological weapon by terrorists.

An army without weapons would be harmless, and so would anthrax without its toxic trio of protein molecules. Working together, they arm the organism for its lethal work.

Following the earlier description of the first two proteins, researchers at the University of Chicago and the Boston Medical Research Institute have discovered the crystal structure of the third. Boston scientist Andrew Bohm is on the team.

"What a crystal structure is, is essentially a map of where all of the atoms are in this toxic protein. With than information in hand, you can see exactly how it's activated, how it does what it's doing, and hopefully how one could go about stopping it," he says.

Just as soldiers have specific jobs in war, so do the three anthrax protein molecules when poisoning a victim.

The first, whose shape was described in 1997, allows the two others to enter cells of the body. The second, described in October, kills immune system cells that would react against anthrax. The third protein, now described in the journal Nature, can be deadly on its own by releasing fluid into the lungs and other infected tissue.

Even in the less serious form of anthrax that infects skin, this third molecule causes limited swelling.

Andrew Bohm says that in the case of a mass anthrax outbreak due to bioterrorism, established antibiotics would remain the first line of defense. But he says any new drugs developed on the basis of the research into the three toxins would go beyond antibiotics in cases where antibiotics are ineffective.

"Antibiotics themselves are fantastic drugs against anthrax. If you are talking about developing new therapeutic approaches to fighting anthrax, you're really just hoping to tip the balance a little bit in favor of the body and against the bacteria, presumably in the very late stages of disease," he says.

Another reason new anthrax drugs are needed is outlined by Harvard Medical School microbiologist John Collier, a researcher who helped describe the shape of one of the anthrax toxins last October.

"If antibiotic resistant strains of the organism fall into the hands of the terrorists and if those are used in an attack, then the antibiotics may be useless to you, in which case you are solely dependent upon other interventions. So from that perspective, it's exceedingly important to develop other approaches to treating anthrax," he says.

The question is whether new drugs could work by combating only one of the anthrax toxins or would have to target two or all three. Researchers have found that the poisonous protein work in combination. For example, the newest one to be described not only causes fluid buildup in the lungs and tissue swelling, but also increases the potency of the one that disables the immune system's defenses.

Biologist Robert Liddington of the Burnham Institute in La Jolla, California writes in a Nature commentary accompanying the latest study that "this molecular teamwork will no doubt be the subject of much future research."

But John Collier at Harvard Medical School found last year that mice can be protected from anthrax by a drug that acts against only a single toxin. The experimental drug interferes with the action of the one that normally allows the other two to enter cells.

"It's an inhibitor that blocks the assembly process. It therefore blocks the action of both of those enzymes (proteins) that act in cells," he explains.

Mr. Collier says pharmaceutical companies are reviewing their library of compounds to determine if any they have already identified can target the anthrax toxins or if they need to develop new drugs.