Ubiquitous protein controls copying of resistant DNA
Staph infections that become resistant to multiple antibiotics don't happen because the bacteria themselves adapt to the drugs, but because of a kind of genetic parasite they carry called a plasmid that helps its host survive the antibiotics.
An atomic force microscopy image shows a four-part complex of the protein RepA (bright mounds) bound together and "handcuffing" two thread-like strands of DNA plasmid.
Credit: University of Nebraska Medical Center Nanoimaging Core Facility
Plasmids are rings of bare DNA containing a handful of genes that are essentially freeloaders, borrowing most of what they need to live from their bacterial host. The plasmids copy themselves and go along for the ride when the bacteria divide to copy themselves.
A team from Duke and the University of Sydney in Australia has solved the structure of a key protein that drives DNA copying in the plasmids that make staphylococcus bacteria antibiotic-resistant. Knowing how this protein works may now help researchers devise new ways to stop the plasmids from spreading antibiotic resistance in staph by preventing the plasmids from copying themselves.
"If plasmids can't replicate, they go away," said lead author Maria Schumacher, an associate professor of biochemistry in the Duke University School of Medicine. "This is a fantastic new target for antibiotics."
The work appears the week of June 9 in the Proceedings of the National Academy of Sciences.
An essential part of biology, plasmids are so minimalistic they're not even considered alive by themselves. But they're good at ferrying genes from one kind of bacteria to another in a process called horizontal gene transfer. They also excel at adapting to environmental conditions more quickly than their bacterial hosts. Plasmids are able to develop new defenses to an antibiotic and then share that new trick with other bacteria.
Through several years of laborious structural biology to figure out the specific shapes of the molecules involved, the research team has mapped out the structure and function of a protein called RepA, which is crucial to the plasmids' ability to copy its DNA and make a new plasmid.
RepA is a protein that sticks to the beginning of the plasmid's DNA sequence and starts the copying process. "This protein is essential to everything," Schumacher said. "If you don't have it, the plasmid will quickly cease to exist."
Plasmids also need a mechanism to prevent themselves from making too many copies, which would strangle their bacterial host. The researchers have found that RepA is crucial to that function as well.
RepA naturally sticks together in pairs. When a pair of RepA proteins bumps into another pair, as when the cell is starting to get crowded with plasmids, the two pairs of RepA preferentially stick to each other. They form a complex back-to-back, with both having their DNA-grabbing parts facing outward.
When RepA forms this four-part molecule, the plasmids are said to be 'handcuffed,' because two rings of DNA are captured with the locked-up and non-functional RepA complex in the middle.
Once it is handcuffed like this, the plasmid will no longer replicate. Schumacher said this mechanism is apparently how RepA prevents the plasmids from overpopulating the bacterial cell.
Schumacher says RepA is ubiquitous in the plasmid world and doesn't bear much resemblance to other proteins, or to human proteins, making it an attractive drug target. She is hopeful the molecule could be a new site to attack with antibiotics.
"This has been a fun project because we saw many things we didn't expect to see," Schumacher said.
The research was supported by the National Institutes of Health and Department of Energy in the U.S., and the National Health and Medical Research Council of Australia.
CITATION: "Mechanism of staphylococcal multiresistance plasmid replication origin assembly by the RepA protein," Maria Schumacher, Nam K. Tonthat, Stephen M. Kwon, Nagababu Chinnam, Michael A. Liu, Ronald A. Skurray and Neville Firth. Proceedings of the National Academy of Sciences, June 9, 2014. DOI: 10.1073/pnas.1406065111
Karl Leif Bates | Eurek Alert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy