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:

(Date:11/2/2015)... PARK, Calif. , Nov. 2, 2015  SRI ... $9 million to provide preclinical development services to the ... the contract, SRI will provide scientific expertise, modern testing ... wide variety of preclinical pharmacology and toxicology studies to ... --> The PREVENT Cancer Drug Development ...
(Date:10/29/2015)... , Oct. 29, 2015  Rubicon Genomics, ... for U.S. distribution of its DNA library preparation ... and Rubicon,s new ThruPLEX Plasma-seq kit. ThruPLEX Plasma-seq ... the preparation of NGS libraries for liquid biopsies--the ... diagnostic and prognostic applications in cancer and other ...
(Date:10/27/2015)... In the present market scenario, security is ... industry verticals such as banking, healthcare, defense, electronic gadgets, ... for secure & simplified access control and growing rate ... of bank accounts, misuse of users, , and so ... laptops, and smartphones are expected to provide potential opportunities ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... Halozyme Therapeutics, Inc. (NASDAQ: HALO ) will be presenting at ... on Wednesday, December 2 at 9:30 a.m. ET/6:30 a.m. PT ... provide a corporate overview. th Annual Oppenheimer Healthcare ... ET/10:00 a.m. PT . Jim Mazzola , vice president ... --> th Annual Oppenheimer Healthcare Conference in ...
(Date:11/24/2015)... ... November 24, 2015 , ... International Society ... one of the premier annual events for pharmaceutical manufacturing: 2015 Annual Meeting. The ... where ISPE hosted the largest number of attendees in more than a decade. ...
(Date:11/24/2015)... -- --> --> ... Market by Product & Services (Primer, Probe, Custom Oligos, ... End-User (Research, Pharmaceutical & Biotech, Diagnostic Labs) - Global ... expected to reach USD 1,918.6 Million by 2020 from ... 10.1% during the forecast period. Browse 183 ...
(Date:11/24/2015)... , November 24, 2015 SHPG ) ... participate in the Piper Jaffray 27 th Annual Healthcare Conference ... December 1, 2015, at 8:30 a.m. EST (1:30 p.m. GMT). ... Chief Financial Officer, will participate in the Piper Jaffray 27 th ... , NY on Tuesday, December 1, 2015, at 8:30 a.m. EST ...
Breaking Biology Technology: