Navigation Links
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 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 o combination therapies, which include compounds that could duplicate the effect caused by the genetic mutation of bacteria together with low-dose antibiotics.

"Bugs are very smart," Woodard said. "It's not a matter of if a bug will become antibiotic resistant, but when. We have to work hard to get ahead of them."


'"/>

Source:University of Michigan


Related biology news :

1. NYU researchers simulate molecular biological clock
2. Vital step in cellular migration described by UCSD medical researchers
3. ASU researchers finds novel chemistry at work to provide parrots vibrant red colors
4. UCSD researchers maintain stem cells without contaminated animal feeder layers
5. Why do insects stop breathing? To avoid damage from too much oxygen, say researchers
6. New protein discovered by Hebrew University researchers
7. First real-time view of developing neurons reveals surprises, say Stanford researchers
8. Agilent Technologies releases automated literature search tool for biology researchers
9. Self-assembled nano-sized probes allow Penn researchers to see tumors through flesh and skin
10. Yale researchers identify molecule for detecting parasitic infection in humans
11. US life expectancy about to decline, researchers say
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:6/16/2016)... , June 16, 2016 ... is expected to reach USD 1.83 billion by ... View Research, Inc. Technological proliferation and increasing demand ... are expected to drive the market growth. ... The development of advanced multimodal techniques ...
(Date:6/7/2016)... June 7, 2016  Syngrafii Inc. and San ... relationship that includes integrating Syngrafii,s patented LongPen™ eSignature ... This collaboration will result in greater convenience for ... union, while maintaining existing document workflow and compliance ... ...
(Date:6/2/2016)... June 2, 2016 Perimeter Surveillance ... Unmanned Systems, Physical Infrastructure, Support & Other Service  ... visiongain offers comprehensive analysis of the global ... will generate revenues of $17.98 billion in 2016. ... Inc, a leader in software and hardware technologies for ...
Breaking Biology News(10 mins):
(Date:6/24/2016)... 2016  Regular discussions on a range of subjects including ... two entities said Poloz. Speaking at a lecture ... , he pointed to the country,s inflation target, which is ... "In certain areas there ... common economic goals, why not sit down and address strategy ...
(Date:6/24/2016)... ... June 24, 2016 , ... While the majority of commercial spectrophotometers and fluorometers ... the 6000i models are higher end machines that use the more unconventional z-dimension of ... beam from the bottom of the cuvette holder. , FireflySci has developed several ...
(Date:6/23/2016)... ... June 23, 2016 , ... ... its second eBook, “Clinical Trials Patient Recruitment and Retention Tips.” Partnering with experienced ... this eBook by providing practical tips, tools, and strategies for clinical researchers. , ...
(Date:6/23/2016)... June 23, 2016   Boston Biomedical , ... compounds designed to target cancer stemness pathways, announced ... granted Orphan Drug Designation from the U.S. Food ... gastric cancer, including gastroesophageal junction (GEJ) cancer. Napabucasin ... to inhibit cancer stemness pathways by targeting STAT3, ...
Breaking Biology Technology: