Last-resort antibiotic gets a new lease on life

For years, vancomycin has been the antibiotic of last resort -- the one doctors used when all others failed. But recent news of patients succumbing to new, vancomycin-resistant strains of bacteria has lent an urgency to efforts to find new drugs to combat these bugs.

Most of the research now underway has focused on finding other drug families that could take vancomycin's place. Assistant professors of pharmacology Paul H. Axelsen, M.D., and Patrick J. Loll, Ph.D., have chosen a different path, one that seeks to modify the structure of vancomycin to restore its effectiveness.

Their approach was made possible by advances in crystallography and in computing over the past decade. In fact, Axelsen's research into vancomycin began as a means of testing the computer programs he was using to model molecules while at the Mayo Clinic in the late 1980s.

"It was an interesting molecule from a chemical point of view," he said. "It was small, it bound to a very specific target and it made for a nice model system to test the accuracy of computer programs."

The rise of vancomycin-resistant bacteria changed Axelsen's project from an "interesting" exercise to a more urgent project.

"In the early '90s, the mechanism by which bacteria resisted vancomycin was described, and strategies to overcome resistance could be developed," he said. "The surface of the bacteria has changed shape. Now we have to change vancomycin so it bonds to that changed shape."

That would not be possible, however, without a detailed structure of the molecule -- which is where Loll comes in. Not long after Axelsen joined the Penn faculty in 1993, Loll arrived on campus with expertise in crystallography, and Axelsen persuaded him to attempt to crystallize vancomycin to analyze its structure.

The structure of the vancomycin molecule, which Loll and Axelsen plan to alter

Axelsen and Loll's work is the first step in an effort to rationally produce a derivative of an existing drug, a relatively new approach in the pharmaceutical field. Until now, new pharmaceuticals have been discovered via a method that Loll described as "Let's try out a bunch of things and see if they work." Recent advances in computing power have made it possible to model specific drug variations that might work against specific bacteria or viruses; a recent example of this approach was the development of protease inhibitors for HIV.

The use of the rational method to modify vancomycin has some clear advantages, the researchers say. One is that none of the other alternate drugs being explored are likely to be as effective over the long run as a vancomycin derivative would be. "We have many bacteria resistant to many common drugs, and these other drugs that are coming up are also showing early signs of resistance developing," Axelsen said.

The other advantage has to do with vancomycin's sheer complexity. "A molecule the size and complexity of vancomycin is one a chemist would not want to get involved with unless they had a very good reason to think that one specific avenue might bear fruit," Loll said. The rational approach can handle the complexity and shorten the search.

So far, the team has successfully analyzed the structure of vancomycin in a crystal, demonstrated how it binds in pairs to its target site on bacteria, and devised computer models that suggest possible modifications of the vancomycin molecule. The next step, once further funds are received, is to actually produce the modified molecules in a lab and test them on bacteria, a task that will be carried out in collaboration with Jeffrey D. Winkler, Ph.D., professor of chemistry.

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