Scientist's Organic Synthesis Techniques Widely Used for Production of Antibiotics

A method of synthetically producing certain antibiotics that also occur in nature has been widely adopted by the pharmaceutical industry.

These techniques, which may be used to produce a whole range of biochemical structures, were developed in the laboratory of Harvard chemist David A. Evans.

"The methods are in active use in many of the pharmaceutical companies, not only in production, but also in discovery," says Evans, who is professor of chemistry and teaches Chemistry 30, "Organic Chemistry."

Researchers at Merck laboratories, where Evans is a regular consultant, are currently using the chemist's techniques to study enzymes involved with HIV, the virus which causes AIDS.

Evans explains that among antibiotics--drugs used to fight bacterial infections in the body--there are three major classes which are structurally very different: penicillins; macrolides, such as erythromycin; and vancomycins.

Research in the chemist's lab focuses on the vancomycins. Like many other antibiotics, vancomycins are produced in nature by the bacteria Streptomyces.

"Vancomycins are particularly suited to treating staph infections, which are not affected by the other classes of antibiotics," says Evans.

"Vancomycins is an amino acid-derived product," Evans says. "We have the chemistry in place for building any amino acid-based products--and rapidly."

These methods mirror the synthesis of the molecules within microorganisms them-selves, Evans says.

"Microorganisms produce these substances as defense," Evans says. "These general families of structures serve to inspire us to develop new techniques."

Evans says that while his research produces one method of creating antibiotics, it may not necessarily create them more easily than current methods, such as fermentation.

Fermentation involves culturing the bacterial cells and then extracting the chemical directly from them. Evans says that the antibiotics are often enhanced by subsequent chemical reactions during the process.

According to Evans, an exciting new area of study in chemical synthesis is the development of small molecules that simulate the catalytic activity of macromolecular enzymes.

Enzymes are proteins produced by organisms that catalyze biochemical reactions, playing a key role in their synthesis.

In the process of synthesizing antibiotics, enzymes within the bacteria act as the catalyst. The smaller molecules can accomplish the same task as the bulkier enzymes.

"This research is on the interface between inorganic chemistry and organic chemistry," Evans says. It makes use of transitional elements of the periodic table such as nickel, samarium, boron, rhodium and iridium.

Evans labels this research as "bioinspirational."

"We are inspired by the elegance of nature's chemical transformations," he says. "There are catalytic activities and fundamental steps which occur in nature which we try to simulate."

Evans says that the synthetic organic chemist has an advantage over nature, in that reaction conditions can be regulated in the laboratory. While in nature, these reactions occur in an "ocean of chemicals," the contents of the test tubes can be controlled in the lab.

To get ideas for new techniques, Evans says, his group first works out a theoretical model or design based on fundamental principles of organic chemistry.

"If the technique works, we build on it," he says. "It is a very iterative process."

Evans says that he also has a great deal of support from his Harvard colleagues, among them 1990 Nobel laureate and Emory Professor of Organic Chemistry Elias J. Corey, Loeb Professor of Chemistry Yoshito Kishi and Professor of Chemistry Stuart L. Schreiber.