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:
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
25.10.2016 | Earth Sciences
25.10.2016 | Power and Electrical Engineering
25.10.2016 | Process Engineering