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Fighting terror, one bacterium at a time
Three RU scientists receive $6 million grant to develop new ways to kill anthrax
The war on terrorism isn’t being fought only in snowy caves and blistering desserts halfway around the world. It’s also occurring in a Petri dish in Rockefeller’s Bronk Laboratory building.
Recently, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, awarded a five-year, $6 million grant to fund the research of three Rockefeller scientists who hope to someday render bioweapons ineffective.
Since 2001, the NIH has annually increased funding of biodefense research by over 400 percent. More than $206 million will be awarded over five years to support research toward this goal. “Per weight, weaponized anthrax is nearly as deadly as a nuclear device, and it is not farfetched to think that terrorists could genetically engineer a bioweapon that is resistant to all currently available antibiotics,” says Rockefeller’s C. Erec Stebbins, head of the Laboratory of Structural Microbiology. Genes that code for resistance to antibiotics are prevalent and could be easily inserted into weaponized organisms using the techniques of molecular biology, he explains.
Stebbins, along with Vincent A. Fischetti, head of the Laboratory of Bacterial Patho-genesis and Immunology, and Alexander Tomasz, Dr. Plutarch Papamarkou Professor and head of the Laboratory of Microbiology, will use the NIH grant to identify new targets for drugs that are less susceptible to antibiotic resistance. To accomplish this task, the team will focus on the bacteriophage, a virus that attacks and violently destroys the anthrax bacterium. Fischetti has already shown, in a research paper published in 2002 in the journal Nature, that a certain enzyme made by the anthrax bacteriophage can annihilate the bacteria with tremendous speed and specificity by destroying the microbes’ cell walls.
Fischetti and colleagues believe that compared to currently available antibiotics, bacterial resistance to these phage enzymes is very rare — and it would be extremely difficult to engineer bacteria that are resistant to them. The bacteriophage enzyme is designed to bind to a critical, unidentified component of the anthrax bacterial cell wall and then cleave the cell wall’s backbone. Since anthrax bacteria require this cell wall component to grow, any mutation in it would be lethal to the microbe.
“The phage have figured out what is critical for anthrax growth and what is not, and it probably took millions of years of evolution to arrive at this single cell wall component,” says Fischetti. Scientists might never have hit on it using traditional drug discovery methods.
Animal trials are already under way at U.S. Defense Department facilities to test the phage enzyme itself in the treatment of anthrax infections — if they prove effective, human trials could follow. But ideally the scientists want to develop a small molecule drug that will accomplish this objective more efficiently. A drug therapy would be easier to produce and administer than the phage enzyme and could be used preventatively.
Tomasz is working to come up with a chemical portrait of the outer surface of the anthrax bacterium. The purpose is to identify the exact structure of the binding site that is recognized by the phage enzyme in the first stage of its selective attack on the bacterium. The nature of this binding component is unsown except that it must be part of the bacterial cell wall, the enormous “supermolecule” which surrounds the bacterium with a network of crosslinked peptides and sugar molecules studded by an unknown number of proteins and other molecules.
Somewhere within the jungle of these surface structures is the component the phage enzyme recognizes and binds to during its attack on the cell wall. The ultimate aim of the Rockefeller scientists is to find that site and determine the molecular pathway responsible for the synthesis of the component to which the phage enzyme binds. This pathway should provide potential new drug targets against this dangerous microbe.

December 12, 2003



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