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Anthrax enzyme images reveal secrets of antibiotic resistance, suggest new drug design

Computer-generated images of a crucial anthrax bacterium enzyme are helping to solve the mystery of how slight mutations in the shape of this protein can make it resistant to the antibiotics called sulfa drugs. These findings, by scientists at St. Jude Children's Research Hospital, appear in the September issue of Structure.

Based on these new insights into the structure of the enzyme, called DHPS, the St. Jude team has also developed a new molecule that appears likely to be able to block the enzyme's activity without triggering resistance.

DHPS normally combines the molecules DHPP and pABA during part of a biochemical pathway that produces folate, a nutrient these bacteria need to survive. Sulfa drugs are antibiotics that block pABA from binding to the enzyme, and thus block folate production.

The St. Jude findings give important clues to how the enzyme binds to DHPP and pABA. They also provide a blueprint of the enzyme that researchers can use to design more effective antibiotics against the bacterium, Bacillus anthracis. Such information is especially valuable because the anthrax bacterium is widely regarded as a potential bioterrorism weapon. The finding could also be the basis for a broad-spectrum antibiotic to treat a variety of other infections that are becoming resistant to these drugs.

The team made these discoveries by creating images of the molecular structure of DHPS using X-ray crystallography. The team bombarded crystals of the enzyme with X-rays, then used the patterns formed by the diffraction of the beams off the crystals to create computer-generated, three-dimensional images of the enzyme shape. The researchers also used this technique to make images of the enzyme bound to the two molecules that the enzyme chemically combines with to make folic acid.

Based on these images of the enzyme and its interaction with other molecules, the investigators discovered how it manipulates pABA and DHPP. In addition, the
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Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
23-Sep-2004


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