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

ve cells have sugars and carbohydrates on the outside in structures that look like hairs.

That exterior protection is part of what makes Gram-negative bacteria harder to kill antibiotics, Woodard said.

Woodard's team set out to genetically modify the cells to eliminate the key sugar to which the hair anchors on the outside of the cell.

"Unfortunately, the bug didn't die," Woodard said. The researchers found that a "backup" gene from a different pathway also could form the anchor, so they knocked out that gene, as well. Initially the cell with both genomic knockouts did not survive without special nutritional supplements. Later, they were surprised to see that with different growth conditions, the cell began to grow again but without the hair-like structure.

The cells survived---but they looked a lot like Gram-positive cells, without all the sugars on the outside.

"We, as well as the entire scientific community, always thought Gram-positive cells could not survive without this external structure. This shows that is not true," Woodard said. Though they didn't die, they were weakened, and that made the cells an easy target for antibiotics.

Because Woodard suspected he might be flying in the face of conventional wisdom on bacteria, he solicited second opinions from the Borstel Research Center in Germany, which does a good deal of work on Gram-negative bacteria. Scientists there were initially skeptical, he said, but eventually, Uwe Mamat and Buko Lindner from Borstel signed on to the project and became co-authors of the current paper.

Other members of the team were U-M medicinal chemistry doctoral students Timothy Meredith and Parag Aggarwal. Meredith, lead author of the publication, has since joined Harvard Medical School as a researcher.

Aggarwal, Mamat and Woodard continue to work on the approach, encouraged by the potential of developing a safer way to treat patients. They hope their research leads t
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Source:University of Michigan


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