Towards the end of March, a New York man became the first person in the United States to die from infection by a strain of bacteria resistant to vancomycin, the powerful antibiotic physicians turn to when others fail. The man was only the fourth known case in the world of resistant staphylococcus aureus infection, and government officials are minimizing the danger to public health represented by this first fatality. Still, the death lends urgency to ongoing efforts by researchers to modify vancomycin in ways that will enable the drug to overcome emerging bacterial resistance.
On the heels of this news, scientists at the University of Pennsylvania Medical Center are reporting a significant advance in the search for new and more effective versions of the antibiotic with the discovery of a novel form of vancomycin. The Penn X-ray crystallography results, published in the May issue of Chemistry & Biology, may explain why certain variant molecules synthesized by chemists at Eli Lilly and Co. show marked activity against vancomycin-resistant bacteria. The findings suggest that the two-molecule vancomycin assembly created at Lilly -- referred to as a dimer -- may be configured in a so-called face-to-face orientation of the molecules rather than the back-to-back arrangement thought to be the norm for vancomycin.
"The whole problem of making a drug that works in this context boils down to one molecule of the drug recognizing and binding specifically to another molecule in the cell wall of the bacteria," explains Patrick J. Loll, PhD, an assistant professor of pharmacology and coauthor on the new report. The resistant bacteria have altered the relevant docking molecule so that the normal vancomycin dimer can no longer bind to it, according to Loll.
"The way vancomycin molecules form into dimers or other larger-order complexes may well play a role in how the drug acts," he says. "These findings suggest a hitherto unsuspected way in which these molecules can associate, opening a new avenue for thinking about how vancomycin actually functions when it binds to bacteria."
Despite the statements of health officials that the case in New York is not cause for alarm, a growing number of scientists are pushing for development of the next generation of antibiotic drugs. They note that bacteria are able to swap drug-resistance genes among species -- in fact, the vancomycin-resistant staphylococcus aureus may have garnered its capability from another, less virulent microbe called enterococcus. Given the fast-paced global spread of the resistant staph -- the first case in the world occurred only in May of last year, in Japan -- there is reason to fear the proliferation of bacteria unresponsive to vancomycin and other current drugs.
"Once a few bacteria become resistant, the resistance factors can become widespread among pathogens," says Paul H. Axelsen, MD, an assistant professor of pharmacology and coauthor with Loll on the Penn study. "These are sentinel cases in New York, Japan, and elsewhere, and I'm concerned that we may not heed the warning. We need to pursue aggressively development of new, more effective drugs that can overcome bacterial resistance."
Loll and Axelsen were the first to describe the structure of vancomycin last year, publishing those results in the February 19, 1997, issue of the Journal of the American Chemical Society -- just before the vancomycin-resistant staph case in Japan was identified. Since then, using the detailed structural information provided by their studies, the scientists have used powerful computational chemistry techniques to design vancomycin variants that might be able to circumvent bacterial resistance. Finding the support needed to synthesize and test the candidate compounds, however, has proven problematic.
"It is difficult to generate enthusiasm in funding agencies or industry for proactive drug research," Axelsen observes. "Even though we can be quite certain that the vancomycin resistance problem will get much worse rather than go away, adequate funding to solve the problem will probably not materialize until it is more generally perceived as an immediate and broad threat to public health."
Recently, Loll and Axelsen teamed up with Penn professor of chemistry Jeffrey D. Winkler, PhD, an accomplished synthetic organic chemist, who will soon begin efforts to synthesize some of the rationally designed compounds.
To analyze the new crystal form, the Penn researchers collaborated with Russ Miller at the Hauptman-Woodward Medical Research Institute, Buffalo, NY, and Charles Weeks at the State University of New York at Buffalo. Miller and Weeks, who have developed specialized computer software for X-ray crystallography, appear as coauthors on the Chemistry & Biology study.
The University of Pennsylvania Medical Center's sponsored research and training ranks third in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $175 million in federal fiscal year 1997. In addition, for the third consecutive year, the institution posted the highest annual growth in these areas -- 17.6 percent -- of the top ten U.S. academic medical centers.
News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page (http://www.med.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the electronic news services SciNews-MedNews and Quadnet.
Journal
Chemistry & Biology