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Viral protein stops anthrax in its tracks


In the climate of terror following September 11, 2001 and the subsequent anthrax attacks propagated through the US mail system, researchers have been feverishly searching for better ways to detect and destroy Bacillus anthracis, the deadly microorganism that causes anthrax. Now, researchers at The Rockefeller University in New York have isolated a novel protein that rapidly and specifically kills the anthrax bacterium.

The protein, called PlyG lysin, instantly kills B. anthracis in cell cultures, but does not harm other closely related strains of bacteria. It represents a new class of antibiotics that may have broad applications in fighting infectious disease. These antibiotics have the potential to kill bacteria without generating antibiotic-resistant strains of infectious microbes.

Micrographs showing effects of PlyG on bacterial cells. View full

"This is a novel way of killing bacteria," says Stephen H. Leppla of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, who wrote a commentary accompanying the findings in tomorrow's issue of Nature. "The strategy uses an enzyme to poke holes in the bacterial cell wall."

Vincent A. Fischetti and two colleagues at Rockefeller University isolated the PlyG lysin from a virus that naturally infects anthrax bacteria. The virus replicates in B. anthracis before breaking open the cell wall to disperse its progeny and infect other bacterial cells. Lysins are enzymes responsible for destroying the cell wall.

The new study builds on work published by Fischetti last year in which his team isolated lysin from Streptococcus pneumoniae. The breakthrough was the realization that lysins may be as effective in attacking bacteria from outside the cell as from within the cell.

"We were surprised that a very small quantity of lysin could kill bacteria instantly," says Fischetti. "This could lead to an earlier diagnosis. Potentially we could identify whether an infectious substance is an anthrax spore in minutes as opposed to hours or days."

The PlyG lysin may also have therapeutic potential in treating anthrax-infected patients. Mice infected with a close relative of B. anthracis typically die within five hours, but when infected mice also receive PlyG, 70 percent recover fully and the rest survives for six to 21 hours. This suggests that PlyG could be an effective agent for treating anthrax infection in humans.

The greatest therapeutic potential for PlyG lies in its ability to kill anthrax bacteria without allowing them to develop resistance. Fischetti and his colleagues tried to culture B. anthracis under conditions in which bacteria usually mutate and become resistant to traditional antibiotics. But when treated in this way with PlyG, the anthrax bacteria were killed and none became resistant to the enzyme treatment.

"This could be especially important in the event of a terrorist attack with resistant organisms," says Fischetti. "The lysin would be the only thing that could kill them." In recent years, a rising problem in treating infectious disease has been the emergence of 'superbugs'—strains of bacteria that resist treatment with standard antibiotics.

The Rockefeller team developed a system for detecting molecules released from B. anthracis cells. The advantage of their system as a way to detect spores is that it does not involve the culturing of bacteria, which is a time-consuming step.

Although it may be years before a diagnostic test or drug is developed from the protein, Leppla predicts there will now be considerable research into the use of lysins in detecting and treating other bacterial infections. "This represents a new class of bacterial killing agents," he says.

Perhaps the most surprising aspect of the new research is that no one had thought of it sooner. Scientists have long known that the viruses, called bacteriophages, specifically target bacterial cells and have evolved mechanisms to avoid bacterial resistance. Scientists have also known that lysins are critical to the infection process.

"Everyone just assumed that these lysins only worked from the inside of the cell," says Fischetti. "We took a chance to see if they would work from the outside as well. This is the coolest work I have ever done."

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Schuch, R. et al. A bacteriolytic agent that detects and kills Bacillus anthracis. Nature 418, 884-889 (August 22, 2002).
Rosovitz, M.J. & S.H. Leppla. Virus deals anthrax a killer blow. Nature 418, 825-826 (August 22, 2002).

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