Most feared among these is staphylococcus aureus, which can result in dangerous respiratory and blood infections -- and, indeed, the appearance in Japan of a vancomycin- resistant strain of this bacterium was reported May 28.
Drug developers are now engaged in an intense race to create new drugs that will prove effective against these bacteria before vancomycin resistance becomes widespread. Recently, University of Pennsylvania Medical Center scientists provided an important key in this effort when they crystallized vancomycin and then used X-ray diffraction analysis to discover the three-dimensional atomic structure of the drug. The advance provides detailed knowledge about the vancomycin molecule to help researchers precisely understand its mechanical and chemical interactions with the bacterial cell-wall molecules it targets.
"Between 5 and 25 percent of enterococcal strains in hospitals nationwide are now resistant to vancomycin, whereas resistance was unheard of only a few years ago," says Paul H. Axelsen, MD, an assistant professor of pharmacology and co-author of a report on the finding in the February 19 issue of the Journal of the American Chemical Society. "And when bacteria become resistant to vancomycin, there is often nothing left that is effective. This structure will be a valuable contribution to the overall effort at designing a new antibiotic effective against vancomycin-resistant bacteria."
Scientists know that bacteria build the strong cell walls they need to survive by cross-linking long cell- surface molecules with other molecules to form a sturdy fibrous mesh. Vancomycin acts by specifically binding to the cross-linking molecule and interfering with wall formation. Resistant bacteria have altered that molecule by substituting a single oxygen atom for a nitrogen atom.
"That very subtle change in the molecule doesn't affect the bacterium's ability to make its cell wall, but it is enough to prevent vancomycin from binding properly," explains Patrick J. Loll, PhD, also an assistant professor of pharmacology and co-author on the study. "Our goal, then, is to see how we can re-engineer the drug so that it can recognize the new form of the target molecule."
The newly elucidated structural information will allow pharmacologists to use a computer-based, rational drug- design process to search for vancomycin variations without having to synthesize compounds in a laboratory for testing.
"For chemists, vancomycin is a difficult drug to modify," says Loll. "If we can use crystallography and computational methods to design and preliminarily test new forms of the drug, we can sidestep a lot of back-breaking chemical synthesis that would otherwise be required in the trial-and-error process of drug development."
Vancomycin was discovered in the 1940s and solving its structure has long been a goal for crystallographers, but the molecule successfully defied their best efforts until now. Progress in researchers' ability to crystallize biological molecules and in computerized analytic techniques laid the groundwork for the breakthrough.
The University of Pennsylvania Medical Center's sponsored
research ranks fifth in the United States, based on grant
support from the National Institutes of Health, the primary
funder of biomedical research in the nation -- $149 million
in federal fiscal year 1996. In addition, for the second
consecutive year, the institution posted the highest growth
rate in its research activity -- 9.1 percent -- of the top
ten U.S. academic medical centers during the same period.
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