May 7, 2004  

POLICIES AND PROCEDURES

 

 

Researchers at SSRL Map New Antibiotic Target

By Kate Metropolis

Addressing one of the world’s pressing health problems, scientists working at SSRL have now obtained detailed information about an enzyme that plays a key role in bacterial self-defense. This advance could lead to a new approach to combating bacterial illnesses, which cause more than 10 million deaths a year.
 

Model of a novel class of antibacterials, superimposed over an example of the data used to discover them. (Image Courtesy of Robert Scott)

After the penicillin family of antibiotics was discovered and developed in the 1940’s, illness and deaths from infectious disease declined dramatically. However, an antibiotic works against specific bacteria for only so long before random mutations (that all bacteria undergo) reduce or eliminate the effectiveness of that particular drug.

Today, according to the Centers for Disease Control, virtually all important bacterial infections throughout the world are rapidly becoming resistant to the antibiotics that have been used to treat them for decades. The Encyclopedia of Life Sciences puts the minimum yearly cost of antibiotic resistance in the U.S. alone at $150 million.

Recently, scientists from the University of Georgia, Utah State University, and Guilford Pharmaceuticals carried out studies at SSRL that could enable drug designers to gain the upper hand—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 bacteria’s cell wall are synthesized 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 also 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 (analysis of extended x-ray absorption fine structure) possible only with synchrotron light 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 the enzyme bound to inhibiting molecules and a glimpse of the enzyme in action.
The work was reported last year in the Journal of the American Chemical Society, vol. 125, no. 48, p. 14654 (http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/2003/125/i48/pdf/ja036650v.pdf)

 

The Stanford Linear Accelerator Center is managed by Stanford University for the US Department of Energy

Last update Tuesday May 04, 2004 by Emily Ball