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http://www.nytimes.com/2002/08/22/science/22ANTH.html

Anthrax Study May Yield Remedy

By NICHOLAS WADE

novel agent that could help detect an anthrax attack and serve as an antidote to the deadly disease has been developed by biologists at Rockefeller University.

The agent was isolated from a virus that preys on the anthrax bacterium and replicates inside it. When the virus particles need to escape, they order the synthesis of a special enzyme called a lysin that chews through the bacterium's cell wall.

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Though designed to pierce the wall from the inside, the lysin enzyme can also crumble it from outside. Doses of lysin injected into mice infected with a close relative of anthrax saved most of the animals from a certain death, according to a report in today's issue of Nature by Dr. Raymond Schuch, Dr. Daniel Nelson and Dr. Vincent A. Fischetti.

The Rockefeller scientists, whose work was financed by the Defense Advanced Research Projects Agency, say the lysin could be used like an antibiotic to treat people who may have been exposed to spores in an anthrax attack. If injected quickly enough, the lysin would destroy the anthrax bacteria in the bloodstream before they had multiplied and released overwhelming amounts of toxin. Attack strains of anthrax can be made resistant to antibiotics, but not to lysin, Dr. Fischetti said.

Much research remains before the enzyme could be used as a drug. But the scientists have a prototype of a lysin-based anthrax detector.

An important feature of the lysin is that it attacks only anthrax and a rare strain of a closely related bacterium, the scientists say. This allows the lysin to be a quick and sensitive detector for anthrax spores that might be used in an attack.

Dr. Schuch said the team had developed a hand-held detection device that would accept an air filtrate or environmental sample. Any anthrax spores are first made to germinate from their protective coat. The lysin is applied to the emerging bacteria, making them spill out their contents. An ingredient of the ruptured cells activates a sample of a firefly enzyme, luciferase, and the flashes of light are amplified for detection.

Dr. Keith Ward, an expert on biological weapon sensors at the Office of Naval Research, described the Rockefeller work as a novel and exciting approach and one that could be extended to other biowarfare agents.

An antibody-based anthrax detector is already in use, but antibodies are hard to make and variable in quality. "We would like something that is faster and more sensitive," Dr. Ward said. The lysin-based method can detect a sample of 2,500 spores in 10 minutes or as few as 100 spores after an hour's reaction time.

Lysins for other dangerous microbes could be added to the sensing devices. The Rockefeller team is already working on lysins from viruses that attack cholera and Yersinia pestis, the agent of plague.

Dr. Fischetti, who has several patents on the lysin method, said it would work for many other species of bacteria because each has its own set of viruses that produce lysins specific for their target bacteria. Lysins could thus provide a whole new class of antibiotics, in his view, and one to which bacteria could not develop resistance.

Resistance is a matter of particular concern to biowarfare experts who fear that attack microbes could be made more lethal by first making them resistant to common antibiotics. The anthrax strain used in last year's attacks was virulent but susceptible to the usual antibiotics. A resistant strain would probably have caused many casualties.

Bacteria can evolve resistance to antibiotics, small chemicals that interfere with various aspects of metabolism. But they cannot evade the lysin, Dr. Fischetti believes, because the attacking virus, over millions of years of evolution, has selected for its target a component the bacterium cannot change.

"The phage has through evolution found the Achilles' heel of every organism," Dr. Fischetti said, using the name for a virus that attacks bacteria.

Dr. Stephen Leppla and Dr. M. J. Rosovitz, two anthrax experts at the National Institutes of Health, said in a commentary in Nature that the lysin approach might help cure infection by an antibiotic-resistant strain of anthrax, although it would need to be injected very quickly before lethal levels of toxin had built up.

A government laboratory is repeating the Rockefeller experiments using the Ames strain of anthrax bacteria, Dr. Schuch said. For convenience, he worked with a special strain of a closely related bacterium, Bacillus cereus, that does not require elaborate safety precautions.

Many steps remain before a usable therapy can be developed from the lysin. The mouse experiments need to be repeated in rabbits and in monkeys, Dr. Schuch said. The lysin would be tested for toxicity in people and could then be stockpiled for use in an attack.

A lysin-based anthrax detector is closer at hand. The Rockefeller team is working with New Horizons Diagnostics, a company in Columbia, Md., to develop a commercial model.

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