By Nancy Ross-Flanigan		Potent antibiotic prospect is found by Pharmacy team
		Reaction catalyzed by KDO 8-P synthase. Diagram: Journal of the American Chemical Society

With growing concerns about drug-resistant bacteria, researchers are scrambling to find effective new antibiotics. After screening some 150,000 compounds, a University of Michigan College of Pharmacy team has found an especially promising prospect-a compound that is 10,000 times more effective than other known inhibitors of a key enzyme in Gram negative bacteria, the researchers report in the Sept. 27 Journal of the American Chemical Society.

Gram negative bacteria include E. coli 0157:H7, the culprit in illness outbreaks linked to eating undercooked hamburger; Legionella, which causes Legionnaires disease, and Vibrio, the bacterium responsible for cholera.

The compound, known as PD 404182, targets an enzyme called KDO 8-P synthase, which plays a vital role in the foliation of antenna-like lipopolysaccharides on the surfaces of bacterial cells. Lipopolysaccharides have numerous functions—helping bacteria defend themselves against antibiotics and host immune responses, for example. By inhibiting KDO 8-P synthase, it should be possible to disrupt lipopolysaccharide synthesis enough to disable or kill the bacteria, scientists reason.

Formula of PD 404182

The U-M team, explains Ronald Woodard, professor of medicinal chemistry and pharmacognosy, tested more than 150,000 compounds for their ability to inhibit KDO 8-P synthase, not knowing the structures or even the identities of the compounds they were testing. Through a series of increasingly specific tests, the U-M group ended up with one compound, PD 404182, that blocked KDO 8-P synthase more effectively than any other known inhibitor of the enzyme.

"This is just an initial finding," Woodard emphasizes. "We've still got a long way to go. But this finding—that it's 10,000 times more potent than compounds that other labs have rationally designed—is very exciting."

After demonstrating the compound's effectiveness in inhibiting the enzyme, Woodard's group tested it on living bacteria. While PD 404182 seemed to weaken the bacteria, it did not kill them. The reason, Woodard believes, is that the compound has a hard time getting into bacterial cells. The challenge now is to modify PD 404182 in ways that will improve that ability.

Woodard's co-workers on the project are doctoral student Matthew Birck and Tod Holler of Parke-Davis Pharmaceutical Research. The work was supported by grants from the National Institutes of Health and in part by funds donated to the U-M College of Pharmacy in memory of Michael Cooperman.