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U-M researchers take new approach to defeating Gram-negative bugs

Ronald Woodard's team set out looking for a way to kill a stubborn type of bacteria and they succeeded---but not in the way he expected.

"We didn't get there the way we thought we'd get there, but in the end, we were right," said Woodard, chair of medicinal chemistry at the University of Michigan College of Pharmacy.

Woodard is senior author of an article describing way he and his research team genetically modified Escherichia coli bacteria, known as a Gram-negative bug, to weaken its defenses. That article appears in the recently released inaugural issue of the American Chemical Society's journal ACS Chemical Biology.

Some of the better-known Gram negatives are salmonella, gonorrhea, cholera and meningicoccal meningitis, along with the bacteria that caused the black plague.

Woodard and his collaborators worked on E. coli in part because it is one of the more common Gram-negative bacteria, and it is considered by researchers the gold standard of Gram-negative bacteria.

After their genetic modifications, E. coli was killed with just a fraction of the antibiotic dose typically needed. It was 512 times more susceptible to Rifampin, 256 times more vulnerable to Novobiocin, and eight times more susceptible to Bacitracin, suggesting doses could be dramatically cut and still be effective, Woodard said. Antibiotics typically only effective against Gram-positive bacteria could work against Gram-negative bacteria if a compound can be designed to mimic this genetic modification, Woodard said.

Also, E. coli can typically withstand the bile salts found in the human digestive tract, but by weakening it, Woodard's team found E. coli would die in the presence of normal levels of bile salts to which the bacteria would be exposed in the human gut.

Besides differing in how they respond to Gram's coloring test, Gram-positive and Gram-negative bacteria look different. Gram-positive cells are smooth on the outside, while Gram-negati
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Source:University of Michigan


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