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 (ACA), 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. This particular strain 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 plasmid – a circular loop of double-stranded DNA within the Staph cell separate from the genome – called 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 cells 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 compound – a blue fluorescent dye used to stain DNA – that 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.
This news release was prepared for the American Crystallographic Association (ACA) by the American Institute of Physics (AIP).
MORE INFORMATION ABOUT THE 2012 ACA MEETINGThe ACA is the largest professional society for crystallography in the United States, and this is its main meeting. All scientific sessions, workshops, poster sessions, and events will be held at the Westin Waterfront Hotel in Boston, Mass.USEFUL LINKS:
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy