Navigation Links
Researchers unveil molecular details of how bacteria propagate antibiotic resistance

Fighting "superbugs" strains of pathogenic bacteria that are impervious to the antibiotics that subdued their predecessor generations has required physicians to seek new and more powerful drugs for their arsenals. Unfortunately, in time, these treatments also can fall prey to the same microbial ability to become drug resistant. Now, a research team at the University of North Carolina at Chapel Hill (UNC) may have found a way to break the cycle that doesn't demand the deployment of a next-generation medical therapy: preventing "superbugs" from genetically propagating drug resistance.

The team will present their findings at the annual meeting of the American Crystallographic Association, held July 28 Aug. 1 in Boston, Mass.

For years, the drug vancomycin has been the last-stand treatment for life-threatening cases of methicilin-resistant Staphylococcus aureus, or MRSA. A powerful antibiotic first isolated in 1953 from soil collected in the jungles of Borneo, vancomycin works by inhibiting formation of the S. aureus cell wall so that it cannot provide structural support and protection. In 2002, however, a strain of S. aureus was isolated from a diabetic kidney dialysis patient that would not succumb to vancomycin. This was the first recorded instance in the United States of vancomycin-resistant Staphylococcus aureus, or VRSA, a deadly variant that many now consider one of the most dangerous bacteria in the world.

Former UNC graduate student Jonathan Edwards (now at the Massachusetts Institute of Technology), under the guidance of chemistry professor Matthew Redinbo, led the research team that sought a detailed biochemical understanding of the VRSA threat. They focused on a S. aureus plasmida circular loop of double-stranded DNA within the Staph cell separate from the genomecalled plW1043 that codes for drug resistance and can be transferred via conjugation ("mating" that involves genetic material passing through a tube from a donor bacterium to a recipient).

Before the plasmid gene for drug resistance can be passed, it must be processed for the transfer. This occurs when a protein called the Nicking Enzyme of Staphylococci, or NES, binds with its active area, known as the relaxase region, to the donor cell plasmid. NES then cuts, or "nicks," one strand of the double helix so that it separates into two single strands of DNA. One moves into the recipient cell while the other remains with the donor. After the two strands are replicated, NES reforms the plasmid in both cells, creating two drug-resistant Staph that are ready to spread their misery further.

Using x-ray crystallography, Edwards, Redinbo and their colleagues defined the structure of both ends of the VRSA NES protein, the N-terminus where the relaxase region resides and the molecule's opposite end known as the C-terminus. They noticed that the N-terminus structure included a region with two distinct protein loops. Suspecting that this area might play a critical role in the VRSA plasmid transfer process, the researchers cut out the loops. This kept the NES relaxase region from clamping onto or staying bound to the plasmid DNA.

Biochemical assays showed that the function of the loops was indeed to keep the relaxase region attached to the plasmid until nicking occurred. This took place, the researchers learned, in the minor groove of a specific DNA sequence on the plasmid.

"We realized that a compound that could block this groove, prevent the NES loops from attaching and inhibit the cleaving of the plasmid DNA into single strands could potentially stop conjugal transfer of drug resistance altogether," Edwards says.

To test their theory in the laboratory, the researchers used a Hoechst compounda blue fluorescent dye used to stain DNAthat could bind to the minor groove. As predicted, blocking the grove prevented nicking of the plasmid DNA sequence.

Redinbo says that this "proof of concept" experiment suggests that the same inhibition might be possible in vivo. "Perhaps by targeting the DNA minor groove, we might make antibiotics more effective against VRSA and other drug-resistant bacteria," he says.


Contact: Catherine Meyers
American Institute of Physics

Related medicine news :

1. Ageless education: Researchers create guide for intergenerational classrooms at nursing homes
2. Miriam researchers urge physicians to ask younger men about erectile dysfunction symptoms
3. John Theurer Cancer Center researchers shed light on new multiple myeloma therapy
4. Mount Sinai researchers discover new target for vaccine development in abundant immune cells
5. Researchers study vaccine as potential weapon against aggressive brain tumors
6. Researchers developing bioadhesive gel to protect women from HIV and HSV infections
7. Researchers find driver of breast cancer stem cell metastasis
8. Researchers unfold the mechanisms underlying blood disorders
9. New lipid screening guidelines for children overly aggressive, UCSF researchers say
10. BUSM researchers identify genetic markers for testosterone, estrogen level regulation
11. UGA researchers develop rapid diagnostic test for pathogens, contaminants
Post Your Comments:
(Date:11/28/2015)... PITTSBURGH, PA (PRWEB) , ... November 28, 2015 , ... ... to the creativity of two inventors, one from Lakewood, New Jersey and the other ... They developed the patent-pending PROTECTOR to save the expense of having to replace NuvaRings ...
(Date:11/28/2015)... CA (PRWEB) , ... November 28, 2015 , ... Pixel ... fully customizable media panels to choose from, the possibilities are endless. Users have full ... more. With the ProPanel: Pulse masking effects, users are sure to get heads to ...
(Date:11/27/2015)... ... November 27, 2015 , ... According to an article ... University of Toronto and the University of British Columbia suggested that laws requiring bicyclists ... The article explains that part of the reason for the controversial conclusion is that, ...
(Date:11/27/2015)... , ... November 27, 2015 , ... A team of ... ways to treat it. Surviving Mesothelioma has just posted the findings on the website. ... Hospital Zurich analyzed the cases of 136 mesothelioma patients who were treated with chemotherapy ...
(Date:11/27/2015)... ... November 27, 2015 , ... Lizzie’s Lice Pickers just announced ... offering customers 10% off of their purchase of lice treatment product. In addition, customers ... According to a company spokesperson. “Finding lice is a sure way to ruin the ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... , November 26, 2015 ... Juntendo universitetssjukhus ser potential att använda ... magnetresonansbilder (MR-bilder) för patienter med multipel ... ett forskningsavtal med SyntheticMR AB för att ... forskningsprojekt på sjukhuset. Med SyMRI kan man ...
(Date:11/26/2015)... 26, 2015 ) ... Administration of High Viscosity Drugs" report to ... announced the addition of the "Self Administration ... offering. --> Research and Markets ( ... "Self Administration of High Viscosity Drugs" ...
(Date:11/25/2015)... DUBLIN , Nov. 25, 2015 /PRNewswire/ ... announced the addition of the "Global ... to their offering. --> ... "Global Brain Monitoring Devices Market 2015-2019" ... Research and Markets ( ) ...
Breaking Medicine Technology: