Ringing in new antibiotic drugs

Updated 10:00 AM Sept. 25, 2006

Ringing in new antibiotic drugs

By Robin Stephenson
Life Sciences Institute

A team of scientists says a new method of developing antibiotics ultimately may lead to new drugs that overcome the defenses of emerging superbugs.

The interdisciplinary team from the U-M Life Sciences Institute and the University of Minnesota School of Pharmacy published two papers in the Oct. 10 edition of the scientific journal Nature Chemical Biology.

Researchers have been studying how some important ring-shaped antibiotics like tetracycline and erythromycin become impotent against superbugs, and how to replenish the arsenal of drugs to fight infections.

U-M researchers David Sherman and Janet Smith and Prof. Robert Fecik from the University of Minnesota are the first known scientists to crystallize an enzyme in the process of closing the antibiotic ring, illustrating exactly how the ring is formed.

"These findings are likely to enable the development of powerful new methods to build structural diversity into large ring systems that are a key component of many types of macrolide antibiotic molecules. This will provide yet another strategy to stay ahead of the emerging and persistent antibiotic resistance threat," Sherman says.

The research should enable scientists to design new catalysts capable of making new macrolide antibiotics.

"Having the tools to make the next generation of macrolide antibiotics is crucial, because these drugs are so well tolerated and have so few side effects," Smith says. "They are really a great class of antibiotics, so we need more of them."

The research team ultimately wants to use these results to make new antibiotics that overcome the defenses of emerging superbugs.

"We're striving to create new drugs that can have a positive impact on the growing threat of infectious diseases." Fecik says. "This type of research can help us make new antibiotic molecules."

Nearly all antibiotics in use today are natural molecules made by bacteria to kill their enemies. The bacteria use specialized proteins called enzymes to carry out the chemical steps in making antibiotic molecules. One way to increase the number of antibiotics for fighting infections is to start where nature stopped and engineer the enzymes to produce new molecules.

But to do this, scientists need to understand how a very large enzyme molecule works on a rather small antibiotic precursor molecule.

Sherman is the John G. Searle Professor of Medicinal Chemistry, Department of Medicinal Chemistry at the U-M College of Pharmacy. Janet Smith is the Margaret J. Hunter Collegiate Professor of Life Sciences, Department of Biological Chemistry, U-M Medical School. Robert Fecik is an assistant professor of medicinal chemistry at the University of Minnesota College of Pharmacy.

The papers are titled "Structural and Mechanistic Insights of Polyketide Macrolactonization from Polyketide-based Affinity Labels," and "Structural Basis for Macrolactonization by the Pikromycin Thioesterase."

Ringing in new antibiotic drugs

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