Doe Science news source
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.
  • 2018-05-31 13:05:25
  • Article ID: 695400

X-Ray Laser Scientists Develop a New Way to Watch Bacteria Attack Antibiotics

The researchers observed how an enzyme from drug-resistant tuberculosis bacteria damages an antibiotic molecule. The new technique provides a powerful tool to examine changes in biological molecules as they happen.

  • Credit: Marius Schmidt / University of Wisconsin Milwaukee

    In a liquid droplet (represented by the light blue circle), an antibiotic disperses through a crystallized protein, beta-lactamase, and binds to it. X-ray snapshots of the bound pair allowed researchers to create maps of the electron density (green) and watch a ring in the antibiotic break open (far right) 30 to 500 milliseconds after the reaction began.

  • Credit: SLAC National Accelerator Laboratory

    The experiment was performed at the Coherent X-ray Imaging (CXI) instrument, which makes use of the rapid, brilliant X-ray pulses from the Linac Coherent Light Source. CXI applies the “diffraction-before-destruction” method to take measurements with ultrashort X-ray pulses before they damage their targets.

  • Credit: Amanda Solliday / SLAC National Accelerator Laboratory

    Cornell University students Andrea Katz and George Calvey prepare a nozzle that acts like a very precise garden hose for delivering a stream of crystallized samples into the X-ray laser beam of the Linac Coherent Light Source.

Tuberculosis, a lung disease that spreads in the air through coughs or sneezes, now kills more people worldwide than any other infectious agent, according to the World Health Organization’s latest global tuberculosis report. And in hundreds of thousands of cases each year, treatment fails because the bacteria that cause Tb have become resistant to antibiotics.

Now an international team of researchers has found a new way to investigate how Tb bacteria inactivate an important family of antibiotics: They watched the process in action for the first time using an X-ray free-electron laser, or XFEL.

In experiments at the Department of Energy’s SLAC National Accelerator Laboratory, they mixed an antibiotic with an enzyme called beta-lactamase that Tb bacteria use, and then watched in real time as the enzyme attacked the antibiotic to deactivate it.

The researchers’ method, called mix-and-inject serial crystallography, takes advantage of the brilliant, ultrafast pulses produced by SLAC’s Linac Coherent Light Source (LCLS). X-ray snapshots taken 30 milliseconds to 2 seconds after the reaction began showed lactamase binding to the antibiotic, ceftriaxone, and bursting one of its chemical bonds.

The results of the experiment were published today in BMC Biology.

“This proof-of-concept study shows that we’re able to see the shape and intermediate stages of the molecules during the process,” says Marius Schmidt, a University of Wisconsin Milwaukee professor who led the experiment. “After decades of trying other techniques in the field of crystallography, the technology is here.”

In crystallography, scientists form a crystal from many copies of a protein and hit the crystal with X-rays to produce a diffraction pattern on a detector, which reveals the protein’s atomic structure. This structure is key to understanding how enzymes and other proteins function.

In the past this only worked with relatively large crystals, which have limited value in this method because the solution containing the antibiotic would take a long time to diffuse into the crystal and react with the enzyme. It is important that the diffusion is faster than the reaction, so that the many protein molecules in the crystal start the chemical process together.

But LCLS and other XFELs have such intense beams that they can capture diffraction patterns from much tinier crystals, a millionth of a meter across or less, Schmidt said, so the antibiotic can get to the enzyme quickly, and the reaction can be recorded with X-rays.

“While there have been elegant studies to observe protein motions with light-induced changes, our work illustrates that a larger class of proteins, namely enzymes, can be investigated in a time-resolved fashion at LCLS and other XFELs,” says Jose Olmos, a doctoral student at Rice University who is one of the principal authors of the publication.

In this study, the research team delivered tiny crystals of beta-lactamase while mixing them with the antibiotic just fractions of a second before they were hit with X-ray pulses.

The team took millions of X-ray snapshots during the reaction and stitched them together to create a map that shows changes in the three-dimensional structure of the antibiotic as it interacts with the enzyme at room temperature.

“For structural biologists, this is how we learn exactly how biology functions,” says Mark Hunter, staff scientist at SLAC and co-author on the study. “We decipher a molecule’s structure at a certain point in time, and it gives us a better idea of how the molecule works.”

In future experiments, taking even more snapshots during the course of the reaction could provide greater detail of the structure and chemical behavior of lactamase. With more information scientists could manipulate the design of antibiotics to prevent such attacks. The experimental method could also be applied to learn the fine details of other types of biological processes where enzymes initiate or steer reactions.

“There’s a large amount of excitement building over this method, because it opens up this new time realm for structural biologists,” Hunter says. Previous work using this technique captured the flipping of an RNA “switch,” important for studies into retroviruses and cancer.

The scientists plan to use the method to look at additional antibiotics. They also intend to take advantage of higher repetition rates – more rapid firing of X-ray pulses – expected at a future upgrade to LCLS and at the recently opened European XFEL. This will allow scientists to capture the data they need in just minutes, compared to days. They could also take more closely spaced snapshots of the reactions, which could give an even more complete picture of the swift chemistry as it happens.

LCLS is a DOE Office of Science User Facility.

The National Science Foundation’s Biology with X-ray Lasers (BioXFEL) Science and Technology Center provided the collaborative framework for this research. In addition to SLAC and the University of Wisconsin Milwaukee, the project included scientists from Arizona State University, Cornell University, Deutsches Elektronen-Synchrotron (DESY), GlaxoSmithKline, Hamburg Center for Ultrafast Imaging, DOE’s Lawrence Livermore National Laboratory, Max Planck Institute for Biochemistry, Milwaukee School of Engineering, Rice University, Seoul National University, University of Hamburg, University of New York Buffalo and 4Marbles, Inc.

Funding for this work came from the DOE Office of Science, Biodesign Center for Applied Structural Discovery at Arizona State University, Helmholtz Association, National Institutes of Health, and the National Science Foundation.


SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, Calif., SLAC is operated by Stanford University for the U.S. Department of Energy's Office of Science. For more information, please visit slac.stanford.edu.

SLAC National Accelerator Laboratory is supported by the Office of Science of the U.S. Department of Energy. 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 science.energy.gov.

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How a Molecular Signal Helps Plant Cells Decide When to Make Oil

Scientists identify new details of how a sugar-signaling molecule helps regulate oil production in plant cells. The work could point to new ways to engineer plants to produce substantial amounts of oil for use as biofuels or in the production of other oil-based products.

Neutrons Produce First Direct 3D Maps of Water During Cell Membrane Fusion

New 3D maps of water distribution during cellular membrane fusion could lead to new treatments for diseases associated with cell fusion. Using neutron diffraction at Oak Ridge National Laboratory, scientists made the first direct observations of water in lipid bilayers modeling cell membrane fusion.

Chemists Demonstrate Sustainable Approach to Carbon Dioxide Capture From Air

Chemists at Oak Ridge National Laboratory have demonstrated a practical, energy-efficient method of capturing carbon dioxide directly from air. If deployed at large scale and coupled to geologic storage, the technique may bolster the portfolio of responses to global climate change.

Nucleation a boon to sustainable nanomanufacturing

Young-Shin Jun, professor of energy, environmental & chemical engineering in the School of Engineering & Applied Science, and Quingun Li, a former doctoral student in her lab, are the first to measure the activation energy and kinetic factors of calcium carbonate's nucleation, both key to predicting and controlling the process.

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Berkeley Lab to Build an Advanced Quantum Computing Testbed

Lawrence Berkeley National Laboratory (Berkeley Lab) will receive $30 million over five years from the U.S. Department of Energy to build and operate an Advanced Quantum Testbed (AQT) allowing researchers to explore superconducting quantum processors to advance scientific research

Cheng wins Midwest Energy News' 40 Under 40 Award

Lei Cheng, an assistant chemist in the Materials Science division at the U.S. Department of Energy's (DOE) Argonne National Laboratory, has received a Midwest Energy News 40 Under 40 Award.

JCESR renewed for another five years

The U.S. Department of Energy (DOE) today announced its decision to renew the Joint Center for Energy Storage Research (JCESR), a DOE Energy Innovation Hub led by Argonne National Laboratory and focused on advancing battery science and technology.

Binghamton designated as NextFlex New York Node for flexible hybrid electronics initiative

NextFlex has designated Binghamton University to be the New York "Node" for its flexible hybrid electronics (FHE) initiative. As the NextFlex New York Node, Binghamton will design, develop and manufacture tools; process materials and products for flexible hybrid electronics; and attract, train and employ an advanced manufacturing workforce, building on the region's existing electronics manufacturing base.

First Particle Tracks Seen in Prototype for International Neutrino Experiment

The largest liquid-argon neutrino detector in the world has just recorded its first particle tracks, signaling the start of a new chapter in the story of the international Deep Underground Neutrino Experiment (DUNE). DUNE's scientific mission is dedicated to unlocking the mysteries of neutrinos, the most abundant (and most mysterious) matter particles in the universe.

Tais Gorkhover Wins LCLS Young Investigator Award for Pioneering Novel X-ray Imaging Methods

Tais Gorkhover, a principal investigator with the Stanford PULSE Institute, will receive the 2018 LCLS Young Investigator Award, granted to early-career scientists in recognition of exceptional research using the Linac Coherent Light Source (LCLS) X-ray free-electron laser at the Department of Energy's SLAC National Accelerator Laboratory.

ORNL, United Kingdom Lab Partner on Nuclear Energy Research

The United Kingdom's National Nuclear Laboratory and the U.S. Department of Energy's Oak Ridge National Laboratory have agreed to cooperate on a wide range of nuclear energy research and development efforts that leverage both organizations' unique expertise and capabilities.

Nat Fisch receives Fusion Power Associates' Distinguished Career Award

Feature describes lifetime career award for PPPL physicist and professor Nat Fisch.

Wells Fargo Innovation Incubator Expands Focus to Include the Food-Water-Energy Interconnection

The Wells Fargo Innovation Incubator (IN2), a technology incubator and platform funded by the Wells Fargo Foundation and administered by the National Renewable Energy Laboratory (NREL), is expanding its program to advance technologies that address the interconnection of food, water and energy.

Graham George receives Lytle Award for contributions to X-ray absorption spectroscopy

Graham Neil George, professor and Canada Research Chair in X-ray Absorption Spectroscopy (XAS) at the University of Saskatchewan, has been chosen to receive the 2018 Farrel W. Lytle Award for his outstanding contributions to synchrotron science at the Department of Energy's SLAC National Accelerator Laboratory.


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Breaking the Symmetry Between Fundamental Forces

Scientists improve our understanding of the relationship between fundamental forces by re-creating the earliest moments of the universe.

Water Plays Unexpected Role in Forming Minerals

Water molecules line up tiny particles to attach and form minerals; understanding how this happens impacts energy extraction and storage along with waste disposal.

Heavy Particles Get Caught Up in the Flow

First direct measurement show how heavy particles containing a charm quark get caught up in the flow of early universe particle soup.

Seeing Between the Atoms

New detector enables electron microscope imaging at record-breaking resolution.

Scaling Up Single-Crystal Graphene

New method can make films of atomically thin carbon that are over a foot long.

Discovered: Optimal Magnetic Fields Suppress Instabilities in Tokamak Plasmas

U.S. and Korean scientists show how to find and use beneficial 3-D field perturbations to stabilize dangerous edge-localized modes in plasma.

New Electron Glasses Sharpen Our View of Atomic-Scale Features

A new approach to atom probe tomography promises more precise and accurate measurements vital to semiconductors used in computers, lasers, detectors, and more.

Getting an Up-Close, 3-D View of Gold Nanostars

Scientists can now measure 3-D structures of tiny particles with properties that hold promise for advanced sensors and diagnostics.

Small, Short-Lived Drops of Early Universe Matter

Particle flow patterns suggest even small-scale collisions create drops of early universe quark-gluon plasma.

Tuning Terahertz Beams with Nanoparticles

Scientists uncover a way to control terahertz radiation using tiny engineered particles in a magnetic field, potentially opening the doors for better medical and environmental sensors.


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