New Clue to How Anthrax Kills

The deadly disease anthrax has been much in the news lately--thanks largely to fears that rogue leaders or terrorists will attempt to wage germ warfare with the anthrax bacillus. But a serendipitous discovery may someday give doctors a new countermeasure against the disease: Researchers report in tomorrow's Science that they have identified a possible mechanism of action for "lethal factor" (LF), a toxic protein produced by the anthrax bacillus that is thought to be one of the principal causes of death in infected individuals.

George Vande Woude and his colleagues at the National Cancer Institute had not set out to study anthrax. They were interested in one of the cell's key signaling pathways, the MAPK pathway, which helps control cell growth, embryonic development, and the maturation of oocytes into eggs. To find out more about the pathway's role in oocyte maturation, Nick Duesbery, a postdoc in Vande Woude's lab, was seeking compounds that block MAPK's activity. They already knew of one such compound, a chemical called PD09859 that is one of 60,000 agents the NCI had screened for ability to block growth of human tumor cells. A search of that database for compounds showing similar effects turned up LF toxin.

Duesbery and company then showed that LF prevents frog oocytes from maturing into eggs, indicating possible blockage of the MAPK pathway. The jam apparently happens, the researchers found, because LF clips off a piece of the enzyme responsible for activating MAPK, thereby crippling it. Although it makes sense that disrupting such a critical pathway could kill cells, researchers still have to show that this effect is what makes LF so toxic.

Even so, the identification of an LF target molecule represents the first step toward identifying compounds that can counteract the toxin--which could be a boon if the anthrax bacillus were to be used in a terrorist attack. "A drug that inhibits LF enzymatic activity might be able to act very quickly to block any further effects of LF on susceptible cells," says microbiologist Randall Holmes of the University of California Health Sciences Center in Denver. Or, as Vande Woude puts it, "Conceivably, we could find a drug that would make anthrax as a weapon of destruction as powerful as a water pistol."