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
Contact: Franklin Hoke
University of Pennsylvania School of Medicine