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Friday, 30 April 2004

Fighting Antibiotic Resistance: New Drug Target Mapped

Nathaniel J. Cosper, David L. Bienvenue, Jacob E. Shokes, Danuta M. Gilner, Takashi Tsukamoto, Robert A. Scott (scott@chem.uga.edu), and Richard C. Holz

Antibiotics and the bacteria they attack are engaged in a constant race to out-evolve one another. An antibiotic is effective against specific bacteria only so long before the random mutations that all bacteria undergo make them resistant to that particular drug. Recently, scientists from the University of Georgia, Utah State University, and Guilford Pharmaceuticals carried out studies at SSRL that could enable drug designers to pull ahead, at least for a while, by developing a new class of antibiotics.

Their work explored a novel antibacterial target: a step in the recipe most bacteria use to create the rigid wall that surrounds and protects individual bacterial cells. Two important components of the cell wall, mDAP and lysine, are synthesized in bacteria by the enzyme DapE. Deleting the gene that encodes DapE has been shown to be lethal to certain bacteria, including the strain that causes stomach ulcers and that appears to be a major cause of stomach cancer, so inhibiting the DapE enzyme looks like a promising approach for drug designers. Because mammals use a different recipe to make their cell walls, an antibiotic that inhibits the DapE enzyme should be toxic to bacteria but not to human cells.

The researchers used a technique possible only with synchrotron light (analysis of extended x-ray absorption fine structure) to map the atomic neighborhood of the chemically active part of the DapE enzyme. This information is important for identifying a chemical component that can lock onto this site and prevent the enzyme from doing its job in production of the cell wall. The investigators also obtained additional information useful in drug design: a view of enzyme bound to inhibiting molecules and a glimpse of the enzyme in action.