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The DOE Science News Source is a Newswise initiative to promote research news from the Office of Science of the DOE to the public and news media.
  • 2017-11-09 11:05:02
  • Article ID: 684933

Resisting the Resistance: Neutrons Search for Clues to Combat Bacterial Threats

  • Credit: SCIstyle/Thomas Splettstoesser

    Bacteria containing enzymes called beta-lactamases, illustrated by the light blue cluster, break down antibiotics and allow bacterial infections to develop and spread through human cells (orange). A team from ORNL’s Neutron Sciences Directorate is using neutrons to study how resistant bacteria, represented by the light blue rod shapes, are evolving to negate the effects of the beta-lactam class of antibiotics.

The discovery of penicillin almost 90 years ago ushered in the age of modern antibiotics, but the growth of antibiotic resistance means bacterial infections like pneumonia and tuberculosis are becoming more difficult to treat.

Researchers at the US Department of Energy’s (DOE’s) Oak Ridge National Laboratory (ORNL) are conducting a series of experiments at ORNL’s Spallation Neutron Source (SNS) to make sense of this phenomenon. Using the MaNDi instrument, SNS beamline 11B, they hope to better understand how bacteria containing enzymes called beta-lactamases resist the beta-lactam class of antibiotics. Any antibiotic containing a beta-lactam ring made up of organic compounds falls under this category.  

“We are looking for answers on a fundamental science level,” said MaNDi instrument scientist Leighton Coates. “We have the machinery to explore these interactions using neutrons.”

With neutrons, the team can observe firsthand how beta-lactamases break down drug compounds without damaging the biological samples. Any insights gleaned from this process could help scientists and physicians detect and mitigate antibiotic resistance in the future.

Beta-lactam antibiotics interfere with penicillin-binding proteins, which are building mechanisms responsible for constructing bacterial cell walls. By disrupting this process, antibiotics destroy invading bacteria and fend off lethal infections.

In response, bacteria have evolved to counteract antibiotics in various ways, but producing beta-lactamases remains their most common and effective tactic. These enzymes serve as natural catalysts, breaking open the beta-lactam rings in antibiotics to deactivate their antibacterial properties.

Beta-lactam antibiotics are commonly prescribed because of their high specificity and low toxicity. However, as the number of antibiotics increases, so too does the number of resistant bacterial strains. Under these circumstances, even common respiratory tract and bloodstream infections can become dangerous.

Patients with existing health problems are more likely to contract bacterial infections and encounter resistant bacteria, but human behavior can contribute to antibiotic resistance in healthy individuals as well, such as when people take unnecessary or expired drugs.

As the perils of bacterial resistance continue to manifest in the emergence of incurable “superbugs” and the reemergence of various infectious diseases once thought under control if not eradicated, scientists are increasingly determined to investigate the contributing factors.  

“We are studying not only how these antibiotics break down, but also how the bacteria are evolving to resist them,” Coates said. 

The researchers are observing this process using capabilities at MaNDi.

“The large detector array on MaNDi, coupled with its high resolution, enables us to collect data over the course of a day or two, whereas on another instrument it would take much longer,” Coates explained.

Such information could help medical professionals and pharmaceutical companies tackle one of the most significant and wide-reaching threats to public health in the world today. The Centers for Disease Control and Prevention estimates that antibiotic resistance affects about 2 million people every year in the United States alone.

Breaking the cycle

Researchers are developing new drugs that rely on substances called inhibitors to block beta-lactamases, but these methods are not infallible.               

Bacteria have fleeting lifespans that allow natural selection to occur at a rapid pace. As a result, beta-lactamases can adapt to attack a new antibiotic shortly after the medication is developed, tested, and introduced. Medical researchers seek to stop, or at least slow, this constant cycle of resistance.

“When a new drug is introduced that the beta-lactamases can’t break down, bacteria quickly mutate and create new enzymes that will then attack the antibiotic,” said Patricia Langan, a postdoctoral researcher at SNS. “It’s a constant battle to stay ahead of them.”

To date, the team has studied how beta-lactamases break down antibiotics like aztreonampenicillin, and cefotaxime.

“We’re going more in-depth into exactly what is happening on a chemical level, and hopefully, our research will help with future inhibitor design and drug development,” Langan said.

Their most significant discovery from this work involves demystifying the catalytic mechanism in beta-lactamases. They studied several key amino acids that help break down beta-lactam antibiotics and identified their roles in this biochemical reaction. By studying proton transfers within these amino acids, the researchers can uncover the inner workings of beta-lactamases.

“We’re finding all sorts of nuances,” Coates said. “By using neutrons, we can work out the protonation state of these important amino acids, and from there we can deduce what’s going on in the catalytic mechanism.”

The research is supported by DOE’s Office of Science. SNS is a DOE Office of Science User Facility. UT-Battelle manages ORNL for the DOE Office of Science. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, please visit—by Elizabeth Rosenthal

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Out of Thin Air

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Rensselaer Polytechnic Institute Professor Jian Shi Receives Air Force Young Investigator Research Program Award

Jian Shi, assistant professor of materials science and engineering at Rensselaer Polytechnic Institute, has won a Young Investigator Research Program (YIP) award from the Air Force Office of Scientific Research (AFOSR). Shi will use the three-year, $450,000 grant to pursue fundamental research on nanoscale complex materials that could lead to the development of next-generation resilient and high-performance energy conversion and sensing technologies.

Kerstin Kleese van Dam Receives 32nd Town of Brookhaven Annual Women's Recognition Award for Science

The award recognizes the contributions Kleese van Dam--director of Brookhaven Lab's Computational Science Initiative since 2015--has made to scientific computing and data management over the past three decades.

Jefferson Lab Announces New Accelerator Science Leader

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First Plasma for New Machine to Study Puzzling Process That Occurs Throughout the Universe

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Rensselaer Polytechnic Institute Professor Jian Sun Receives Power Electronics Achievement Award

Jian Sun, professor of electrical, computer, and systems engineering and director the New York State Center for Future Energy Systems at Rensselaer Polytechnic Institute, received the 2017 R. David Middlebrook Outstanding Achievement Award from the IEEE Power Electronics Society (PELS). He was recognized for "contributions to modeling and control of power electronic converters and systems."

FGC Plasma Solutions Wins Top NASA Innovation Award

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Sandia Researcher Jacqueline Chen Elected to National Academy of Engineering

LIVERMORE, Calif. -- Jacqueline Chen, a distinguished member of the technical staff at Sandia National Laboratories, has been elected to the National Academy of Engineering. Chen is among the 99 new members from around the globe in the 2018 class.Election to the National Academy of Engineering is the highest professional distinction for an engineer in the United States.

PNNL Helps Form International Energy Storage Organization

News Release DALIAN, China -- Energy storage allows power operators across the nation to balance electricity supply and demand instantaneously, affording ratepayers a more resilient power supply.Now the focus on energy storage is global. In January, energy storage experts at the Department of Energy's Pacific Northwest National Laboratory joined forces with their counterparts around the world to forge the International Coalition for Energy Storage and Innovation, or ICESI.

University Partnership to Help Nevada Scientists Commercialize Discovery

UNLV's Office of Technology Transfer and the Desert Research are partnering to help faculty and students leverage each other's talent and resources to transform inventions into new products and services.

DOE Seeks Industry Partners for HPC Research on Materials in Applied Energy Technologies

The Department of Energy (DOE) today announced a funding opportunity totaling $3 million to support projects between U.S. industry and DOE national laboratories related to improving materials in severe or complex environments through the new High Performance Computing for Materials in Applied Energy Technologies (HPC4Mtls) Program.

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Turning Up the Heat on Remote Research Plots Without Electricity

Flexible, tunable technique warms plants without need for electricity, aiding ecosystem research in remote locales.

Engineering Yeast Tolerance to a Promising Biomass Deconstruction Solvent

Chemical genomic-guided engineering of gamma-valerolactone-tolerant yeast.

Saplings Survive Droughts via Storage

Certain species of trees retain stored water, limit root growth to survive three months without water.

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Intuitive visual analytical model better explains complex architectural scenarios and offers general design principles.

Data Dive: How Microbes Handle Poor Nutrition in Tropical Soil

High-performance computing reveals the relationship between DNA and phosphorous uptake.

The Secret Lives of Cells

Supercomputer simulations predict how E. coli adapts to environmental stresses.

It's Not Part of the Problem, but Part of the Solution

Americium(III) is selectively and efficiently separated from europium(III) by an extractant in an ionic liquid.

Buckyball Marries Graphene

Electronic and structure richness arise from the merger of semiconducting molecules of carbon buckyballs and 2-D graphene.

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Tracking atoms is crucial to improving the efficiency of next-generation perovskite solar cells.

Catalysts: High Performance Lies on the Edge

Iron may be more valuable than platinum. Sometimes.


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