ANN ARBOR---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 O157: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 formation 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.
Other research groups have tried to develop KDO 8-P synthase inhibitors through "rational drug design"---designing compounds that closely resemble the molecules that normally bind to the enzyme. But the U-M team took a different approach, explains Ronald Woodard, professor of medicinal chemistry and pharmacognosy. They 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, which 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 modify PD 404182 in ways that will improve that ability. To that end, the researchers are using computer models and X-ray crystallography data, provided by Domenico Gatti of Wayne State University in Detroit, to better understand the structure of PD 404182 and how it interacts with the enzyme it inhibits. They also hope to screen other compounds in the same family as PD 404182 for more clues to how structure affects activity.
Woodard's co-workers on the project are Matthew Birck, a doctoral student in the College of Pharmacy's Medicinal Chemistry Program, and Tod Holler of Parke-Davis Pharmaceutical Research, a division of Warner-Lambert (now Pfizer). 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.
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