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New method for screening potential anthrax drugs
  

 

To speed the search for improved anthrax drugs, researchers have created a new method for finding inhibitors of the most dangerous toxin produced during anthrax infections. The toxin continues to wreak havoc on human cells even after the bacterium has died. This means that even if antibiotics clear a person's bloodstream of Bacillus anthracis, toxins remain.


Bacillus anthracis

The method can be used to screen drug libraries for compounds that neutralize the toxin by inhibiting the lethal factor protein. Lethal factor—one of three proteins in the anthrax toxin—is the main virulence factor of Bacillus anthracis. Lethal factor is a protease and cleaves other proteins. The uncontrolled cutting of human proteins by lethal factor destroys the cell.

"It's clear that even if antibiotics clear anthrax bacteria from a person's bloodstream there are still toxins present," says Jeffrey D. Hermes, who led the project at Merck Research Laboratories in Rahway, New Jersey. "That's what we are up against."

The test uses a fluorescent 'substrate' to indicate the activity of lethal factor protease. Two fluorescent probes are attached to a synthesized target—a small peptide that looks like proteins cleaved by lethal factor in human cells. The cutting of the target molecule produces a fluorescent glow.

The strengths of the new method are its sensitivity and speed, according to Hermes. The test requires very small amounts of lethal factor, and researchers can screen many compounds simultaneously in plates containing lethal factor and the synthesized molecule.

The method is described in Proceedings of the National Academy of Sciences. "Merck has a philosophy that research tools should be made available to the entire scientific community," says Hermes. This is particularly important in the case of anthrax, he adds, because pharmaceutical, biotech, or academic laboratories may already have compounds that inhibit lethal factor on their shelves.

See related GNN articles
»Florida Anthrax Bacterium Sequenced
»Structure of the third deadly anthrax protein

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Cummings, R.T. et al. A peptide-based fluorescence resonance energy transfer assay for Bacillus anthracis lethal factor protease. Proc Natl Acad Sci USA 99, 6603-6606 (May 14, 2002). Published online May 7, 2002.
 

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