Breakthrough could lead to drugs that better combat 'superbugs'

ORIGINAL: Argonne National Lab

BY JEN SALAZAR

February 28, 2013

NDM-1, present in a number of pathogenic bacteria, including Klebsiella pneumonia and Escherichia coli, is able to defeat many of the world’s most widely used antibiotics, including penicillin derivatives, cephalosporins, monobactams and carbapenems.

LEMONT, Ill. – In the never-ending battle between antibiotic developers and the bacteria they fight, scientists at the U.S. Department of Energy’s (DOE) Argonne National Laboratory have made a key breakthrough that could allow for the development of new drugs to more effectively combat antibiotic-resistant “superbugs.”

An Argonne team led by Youngchang Kim of the Structural Biology Center, in collaboration with researchers from the Midwest Center for Structural Genomics, the University of Texas-Pan American and Texas A&M University, recently determined the structure of NDM-1, a harmful enzyme able to overcome several antibiotics. The team used a combination of X-ray crystallography at Argonne’s Advanced Photon Source (APS), biochemical assays, and computational modeling using resources at two Texas universities.

Structure of NDM-1 in complex with two cadmium ions and ampicillin. The intermediate (int-amp) is superposed with the modeled unhydrolyzed ampicillin (yellow).

NDM-1, present in a number of pathogenic bacteria, including Klebsiella pneumonia and Escherichia coli, is able to defeat many of the world’s most widely used antibiotics, including penicillin derivatives, cephalosporins, monobactams and carbapenems. The enzyme works by effectively binding to and breaking – in a process known as hydrolysis – a structure called a β-lactam ring, which is necessary for antibiotics to function.

The traditional view of enzymes, particularly those most essential for the bacteria to survive, is that they have a very specific substrate (or target – in this case the antibiotic) to bind and act on, and they interact with this target directly by forming a well-fitted lock-and-key-like complex. However NDM-1, and others like it, can act on a broad range of substrates.

“These kinds of enzymes can recognize many different targets,” said Andrzej Joachimiak, head of Argonne’s Structural Biology Center and the Midwest Center for Structural Genomics.

“The appearance of NDM-1 among pathogenic bacteria represents a major concern because the enzyme can inactivate so many of the antibiotics that we use to treat infections,” said Charles Edmonds of the National Institutes of Health’s National Institute of General Medical Sciences, which partially supported the study. “This work, by providing a detailed understanding of the structure of the enzyme and its mechanism of action, brings an invaluable tool to the design of new drugs to combat this significant threat to public health.”

The act of NDM-1 binding to the antibiotic, however, does not represent the entire story, because for the enzyme to effectively overcome the antibiotic, it must also cleave the β-lactam ring. The researchers found that certain metals, including zinc, manganese and cadmium, can bind to the NDM-1 active site – and to the β-lactam ring. While zinc provides the most favorable environment for cleavage to occur, cadmium tends to inhibit the enzyme’s ability to cleave the ring.

“The next step in the research is to look for inhibitors that we can create that would block the functioning of the enzyme,” Joachimiak said. “If we can stop the enzyme from cutting the ring, the antibiotics stand a much better chance of staying effective.”

The results of the research were recently published in The FASEB Journal in an article titled “NDM-1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism.”

The research was supported by the National Institutes of Health and the National Science Foundation. The APS and the Argonne Structural Biology Center are supported by DOE’s Office of Science, while the Argonne Midwest Center for Structural Genomics is supported by the National Institutes of Health. The researchers also used computational resources at the University of Texas at Austin and the University of Texas-Pan American.

Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation's first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America's scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy's Office of Science.- See more at: http://www.anl.gov/articles/breakthrough-could-lead-drugs-better-combat-superbugs#sthash.exRUc0SD.dpuf

Bloom - Microbial Bebop

ORIGINAL: YouTube

This musical composition was created from data of microbes (bacteria, algae and other microorganisms) sampled in the English Channel. Argonne National Laboratory biologist Peter Larsen created the songs as a unique way to present and comprehend large datasets. 

This composition highlights seasonal patterns in marine physical parameters at the L4 Station. The chords are generated from seasonal changes in photosynthetically active radiation. The melody of each measure is comprised of eight notes, each mapped to a physical environmental parameter, in the following order: 

• temperature, 
• soluble reactive phosphate, 
• nitrate, 
• nitrite, 
• saline, 
• silicate and c
• hlorophyll A concentrations. 

More information at http://www.anl.gov/articles/songs-key-sea

Photo of cyanobacteria colonies is courtesy Specious Reasons

(http://www.flickr.com/photos/28594931@N03/4726914132/) at Flickr via 

Creative Commons.

Supercomputer Recreates Universe From Big Bang to Today

ORIGINAL: Space

Clara Moskowitz, SPACE.com Assistant Managing Editor

11 September 2012

Large-scale structures in the universe form over time in these stills from a supercomputer simulation of the evolution of the universe.

CREDIT: Habib et al./Argonne National Lab 

Scientists would love to be able to rewind the universe and watch what happened from the start. Since that's not possible, researchers must create their own mini-universes inside computers and unleash the laws of physics on them, to study their evolution.

Now researchers are planning the most detailed, largest-scale simulation of this kind to date. One of the main mysteries they hope to solve with it is the origin of the dark energy that's causing the universe to accelerate in its expansion.

The new simulation is a project led by physicists Salman Habib and Katrin Heitmann of Illinois' Argonne National Laboratory, and will run on the lab's Mira supercomputer, the third-fastest computer in the world, starting in the next month or two. The program will use trillions of "particles" — elements in the simulation that stand in for small bits of matter. The computer will let time run, and watch as the particles move through space in response to the forces acting on them.

As the simulation progresses, these bits of matter will clump together under gravity to form larger and larger blobs representing galaxies, galaxy clusters and superclusters. To evolve the universe from the Big Bang 13.7 billion years forward to today, the simulation will take up to two weeks. [Video: Simulation of the Universe from Big Bang to Now]

Testing the theory

The ultimate goal is to compare the best telescope observations of structure in the universe to the structure displayed in the computer model, to test the reigning theory of cosmology.

"We are trying to look for subtle ways in which it's wrong," Habib told SPACE.com. "That’s why you need these very high-resolution, very large-scale simulations to see if the observations don't match the predictions."

Dark energy is the name given to whatever is causing the expansion of the universe to accelerate. When this acceleration was first discovered in the 1990s, it shocked the science community, because theories predicted the universe's expansion would be steady or slowing down, because of the inward pull of gravity.

The current reigning theory posits that dark energy is what's called the cosmological constant, a term Einstein first thought to put into his equations of general relativity to represent the vacuum energy of the universe. Although Einstein ultimately decided not to include the term, scientists later realized that it could explain the current observations of the expansion of the universe.

However, cosmologists aren't satisfied with this explanation, Habib said.

Another possibility

"It's just a single number entered as an extra term in the equations," he said. "The problem is that if you ask what its value should be, it's enormous — many orders of magnitude bigger than what is actually observed."

While simulations based on the cosmological constant so far appear to match what's seen in large-scale observations of the universe, scientists think that next-generation observations may reveal discrepant details.

If a cosmological constant is not to blame for the accelerated expansion of the universe, another possibility is that space contains some other type of mass or energy, such as a field, that is pulling everything apart.

"It's basically guesswork; it could be like this, or it could be like that," Habib said. "Either way it's very interesting."

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