The next enchanted ring?

The active component of the wonder drug penicillin and related antibiotics such as the cephalosporins is an “enchanted ring,” called the β-lactam ring. Antibiotics that include these rings are arguably the most important drugs in human history, having singlehandedly increased global life expectancy by an estimated five years.

“People often say we’re running out of antibiotics, but there are more than 20,000 molecules with antibiotic activity in the Handbook of Antibiotics,” said Timothy Wencewicz, a chemist at Washington University in St. Louis who specializes in antibiotic design.

“Fewer than 1 percent of those has ever been considered as a potential clinical candidate. They languish because it takes so much time and care to prepare a molecule for use as a pharmaceutical.”

Wencewicz carefully chose one of these molecules, obafluorin, for further study. Oblafluorin, discovered in 1984 by the Squibb Institute, is made by a fluorescent strain of soil bacteria that forms biofilms on plant roots.

Like penicillin, obafluorin has a four-membered ring. A four-membered ring puts strain on the bond angles that carbon prefers to adopt, explains Wencewicz. “The strain turns these rings into molecular bombs that go off when they are put in the right place at the right time, which is useful for killing microbes,” he said.

But because a four-member ring is unstable, these molecules are also short lived and hard to make. It took years for chemists to learn how to synthesize penicillin from chemicals and then to figure out how fungi make it. The antibiotic is still made by fermenting a penicillin-exuding strain of fungus in giant stainless steel vats.

The Wencewicz lab was able to leapfrog the whole process, using genetics to zero in on the biosynthetic machinery that bacteria use to make obafluorin and then to reconstruct that multi-step, enzyme-catalyzed process in the lab.

Wencewicz, graduate students Mars Reck and Jason Schaffer, and undergraduate Neha Prasad describe the complete biosynthetic machinery for the assembly of the ß-lactone obafluorin in the May 15 issue of Nature Chemical Biology.

The ß-lactones inhibit a large class of enzymes called the serine hydrolases. “There are hundreds of known serine hydrolases, and they are implicated in many human diseases,” Wencewicz said. The ß-lactones may prove useful in the treatment of cancer and obesity, as well as infectious diseases.

Continue reading the original article in The Source.

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