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News Article | May 3, 2017
Site: www.eurekalert.org

Antibiotic resistance is a growing global health threat. So much so that a 2014 study commissioned by the Prime Minister of the United Kingdom predicted that, if the problem is left unchecked, in less than 35 years more people will die from antibiotic resistant superbugs than from cancer. It is critical that researchers develop new antibiotics informed by knowledge of how superbugs are resistant to this medication. To help on this front, in a new paper published in the journal Structure, researchers from McGill University present in atomic detail how specific bacterial enzymes, known as kinases, confer resistance to macrolide antibiotics, a widely used class of antibiotics and an alternative medication for patients with penicillin allergies. The study shows for the first time how these kinases recognize and chemically destroy macrolide antibiotics. While these kinases were known previously to scientists, uncovering precisely how they work at a chemical and structural level was not an easy process. "In 2009 we began cloning and trying to produce large amounts of these enzymes for our studies," explains Dr. Albert Berghuis, Chair of the Department of Biochemistry at McGill University's Faculty of Medicine and the study's senior author. After over a year of tweaking the process to assemble enough material, the next step was trying to make "kinase" crystals, similar to sugar crystals. These were then irradiated with X-rays at the Canadian Light Source in Saskatoon. It took an additional three years to generate these crystals and analyze the data from Saskatchewan. "This finally provided us with an atomic view of the kinases and how they bind different macrolide antibiotics," Dr. Berghuis says. Yet this atomic level image was analogous to a picture of a complex machine that incorporates unfamiliar technology, he adds. The image didn't explain how that machine actually works. As a result, almost three more years were required to figure out how the different parts of the kinase confer resistance to different macrolide antibiotics. The researchers found that the kinase enzymes have an impressive ability to confer resistance to many different macrolide antibiotics -- the two enzymes that were studied in detail are essentially able to confer resistance to all macrolide antibiotics currently in use. "In the end, we now know exactly how superbugs confer resistance to macrolides using these kinases," explains Dr. Berghuis. "This allows us to make small changes to these antibiotics such that the kinases can no longer interact with these drugs, which will make the next-generation antibiotics less susceptible to resistance by superbugs." The next steps will be to develop these new and improved macrolide antibiotics --, which Dr. Berghuis estimates will take another two to three years -- and to then test them. But this is only one element needed to combat the growing prevalence of superbugs. "Antibiotic resistance is a multi-faceted problem, and our research is one aspect that should be placed in the context of other components, such as curtailing the over-use of antibiotics," notes Dr. Berghuis. "Only when a comprehensive multi-pronged strategy is used can we hope to successfully address this global health threat." This research was funded by the Canadian Institutes of Health Research (CIHR) with assistance from the Canadian Macromolecular Crystallography Facility at the Canadian Light Source in Saskatoon. The article "Structural Basis for Kinase-mediated Macrolide Antibiotic Resistance" was published in the journal Structure on May 2, 2017. DOI: 10.1016/j.str.2017.03.007


News Article | May 4, 2017
Site: www.rdmag.com

The growing threat of antibiotic resistant bacteria has led researchers around the globe to look at ways to stop these ‘superbugs’. Researchers from McGill University in Montreal have presented in detail how specific bacterial enzymes called kinases, confer resistance to macrolide antibiotics—a widely used class of antibiotics and an alternative medication for patients with penicillin allergies. They showed for the first time how kinases recognize and chemically destroy macrolide antibiotics. Scientists only recently began to understand how kinases work at the chemical and structural level. “In 2009 we began cloning and trying to produce large amounts of these enzymes for our studies,” Albert Berghuis, Ph.D., chair of the Department of Biochemistry at McGill University’s Faculty of Medicine and the study’s senior author, said in a statement. Berghuis’ team tweaked the process for over a year to assemble enough material and then tried to make kinase crystals, which were irradiated with X-rays at the Canadian Light Source in Saskatoon. The researchers then generated crystals and analyzed the data for the next three years. “This finally provided us with an atomic view of the kinases and how they bind different macrolide antibiotics,” Berghuis said. The researchers discovered that the kinase enzymes have the ability to confer resistance to many different macrolide antibiotics and the two enzymes selected in the study were able to confer resistance to all macrolide antibiotics currently in use. “In the end, we now know exactly how superbugs confer resistance to macrolides using these kinases,” Berghuis said. “This allows us to make small changes to these antibiotics such that the kinases can no longer interact with these drugs, which will make the next-generation antibiotics less susceptible to resistance by superbugs.” The researchers now plan on developing and testing the new macrolide antibiotics over the course of the next two or three years. According to a 2014 study in the U.K., that if left unchecked more people will die from antibiotic resistant superbugs than from cancer by 2050. “Antibiotic resistance is a multi-faceted problem, and our research is one aspect that should be placed in the context of other components, such as curtailing the over-use of antibiotics,” Berghuis said. “Only when a comprehensive multi-pronged strategy is used can we hope to successfully address this global health threat.” The study was published in Structure.


News Article | May 4, 2017
Site: www.rdmag.com

The growing threat of antibiotic resistant bacteria has led researchers around the globe to look at ways to stop these ‘superbugs’. Researchers from McGill University in Montreal have presented in detail how specific bacterial enzymes called kinases, confer resistance to macrolide antibiotics—a widely used class of antibiotics and an alternative medication for patients with penicillin allergies. They showed for the first time how kinases recognize and chemically destroy macrolide antibiotics. Scientists only recently began to understand how kinases work at the chemical and structural level. “In 2009 we began cloning and trying to produce large amounts of these enzymes for our studies,” Albert Berghuis, Ph.D., chair of the Department of Biochemistry at McGill University’s Faculty of Medicine and the study’s senior author, said in a statement. Berghuis’ team tweaked the process for over a year to assemble enough material and then tried to make kinase crystals, which were irradiated with X-rays at the Canadian Light Source in Saskatoon. The researchers then generated crystals and analyzed the data for the next three years. “This finally provided us with an atomic view of the kinases and how they bind different macrolide antibiotics,” Berghuis said. The researchers discovered that the kinase enzymes have the ability to confer resistance to many different macrolide antibiotics and the two enzymes selected in the study were able to confer resistance to all macrolide antibiotics currently in use. “In the end, we now know exactly how superbugs confer resistance to macrolides using these kinases,” Berghuis said. “This allows us to make small changes to these antibiotics such that the kinases can no longer interact with these drugs, which will make the next-generation antibiotics less susceptible to resistance by superbugs.” The researchers now plan on developing and testing the new macrolide antibiotics over the course of the next two or three years. According to a 2014 study in the U.K., that if left unchecked more people will die from antibiotic resistant superbugs than from cancer by 2050. “Antibiotic resistance is a multi-faceted problem, and our research is one aspect that should be placed in the context of other components, such as curtailing the over-use of antibiotics,” Berghuis said. “Only when a comprehensive multi-pronged strategy is used can we hope to successfully address this global health threat.” The study was published in Structure.


News Article | May 3, 2017
Site: phys.org

Antibiotic resistance is a growing global health threat. So much so that a 2014 study commissioned by the Prime Minister of the United Kingdom predicted that, if the problem is left unchecked, in less than 35 years more people will die from antibiotic resistant superbugs than from cancer. It is critical that researchers develop new antibiotics informed by knowledge of how superbugs are resistant to this medication. To help on this front, in a new paper published in the journal Structure, researchers from McGill University present in atomic detail how specific bacterial enzymes, known as kinases, confer resistance to macrolide antibiotics, a widely used class of antibiotics and an alternative medication for patients with penicillin allergies. The study shows for the first time how these kinases recognize and chemically destroy macrolide antibiotics. A discovery seven years in the making While these kinases were known previously to scientists, uncovering precisely how they work at a chemical and structural level was not an easy process. "In 2009 we began cloning and trying to produce large amounts of these enzymes for our studies," explains Dr. Albert Berghuis, Chair of the Department of Biochemistry at McGill University's Faculty of Medicine and the study's senior author. After over a year of tweaking the process to assemble enough material, the next step was trying to make "kinase" crystals, similar to sugar crystals. These were then irradiated with X-rays at the Canadian Light Source in Saskatoon. It took an additional three years to generate these crystals and analyze the data from Saskatchewan. "This finally provided us with an atomic view of the kinases and how they bind different macrolide antibiotics," Dr. Berghuis says. Yet this atomic level image was analogous to a picture of a complex machine that incorporates unfamiliar technology, he adds. The image didn't explain how that machine actually works. As a result, almost three more years were required to figure out how the different parts of the kinase confer resistance to different macrolide antibiotics. Leveraging this new knowledge in future drug design The researchers found that the kinase enzymes have an impressive ability to confer resistance to many different macrolide antibiotics—the two enzymes that were studied in detail are essentially able to confer resistance to all macrolide antibiotics currently in use. "In the end, we now know exactly how superbugs confer resistance to macrolides using these kinases," explains Dr. Berghuis. "This allows us to make small changes to these antibiotics such that the kinases can no longer interact with these drugs, which will make the next-generation antibiotics less susceptible to resistance by superbugs." The next steps will be to develop these new and improved macrolide antibiotics —, which Dr. Berghuis estimates will take another two to three years—and to then test them. But this is only one element needed to combat the growing prevalence of superbugs. "Antibiotic resistance is a multi-faceted problem, and our research is one aspect that should be placed in the context of other components, such as curtailing the over-use of antibiotics," notes Dr. Berghuis. "Only when a comprehensive multi-pronged strategy is used can we hope to successfully address this global health threat." Explore further: It's false to believe that antibiotic resistance is only a problem in hospitals – GP surgeries are seeing it too More information: Desiree H. Fong et al, Structural Basis for Kinase-Mediated Macrolide Antibiotic Resistance, Structure (2017). DOI: 10.1016/j.str.2017.03.007


Gallant B.M.,Massachusetts Institute of Technology | Kwabi D.G.,Massachusetts Institute of Technology | Mitchell R.R.,Massachusetts Institute of Technology | Zhou J.,Canadian Light Source Inc. | And 2 more authors.
Energy and Environmental Science | Year: 2013

Understanding the origins of high overpotentials required for Li 2O2 oxidation in Li-O2 batteries is critical for developing practical devices with improved round-trip efficiency. While a number of studies have reported different Li2O2 morphologies formed during discharge, the influence of the morphology and structure of Li2O2 on the oxygen evolution reaction (OER) kinetics and pathways is not known. Here, we show that two characteristic Li2O2 morphologies are formed in carbon nanotube (CNT) electrodes in a 1,2-dimethoxyethane (DME) electrolyte: discs/toroids (50-200 nm) at low rates/overpotentials (10 mA gC-1 or E > 2.7 V vs. Li), or small particles (<20 nm) at higher rates/overpotentials. Upon galvanostatic charging, small particles exhibit a sloping profile with low overpotential (<4 V) while discs exhibit a two-stage process involving an initially sloping region followed by a voltage plateau. Potentiostatic intermittent titration technique (PITT) measurements reveal that charging in the sloping region corresponds to solid solution-like delithiation, whereas the voltage plateau (E = 3.4 V vs. Li) corresponds to two-phase oxidation. The marked differences in charging profiles are attributed to differences in surface structure, as supported by X-ray absorption near edge structure (XANES) data showing that oxygen anions on disc surfaces have LiO2-like electronic features while those on the particle surfaces are more bulk Li 2O2-like with modified electronic structure compared to commercial Li2O2. Such an integrated structural, chemical, and morphological approach to understanding the OER kinetics provides new insights into the desirable discharge product structure for charging at lower overpotentials. © 2013 The Royal Society of Chemistry.


Wang J.,Canadian Light Source Inc. | Zhou J.,Canadian Light Source Inc. | Hu Y.,Canadian Light Source Inc. | Regier T.,Canadian Light Source Inc.
Energy and Environmental Science | Year: 2013

Scanning transmission X-ray microscopy (STXM) has been used to investigate the chemical, electronic and structural nature of Co3O4 nanocrystals grown on single nitrogen-doped graphene sheets through spatially resolved X-ray absorption near edge structure (XANES) spectroscopy and chemical imaging. It has been found that Co3O4 nanocrystals grown on N-doped graphene were partially reduced via Co3+(Oh) to Co2+(Oh), and the reduction varies spatially on and among individual Co3O4 nanocrystal-graphene sheets. Nitrogen sites on graphene have been shown to be major and important anchoring sites for Co3O4 nanocrystals in addition to the carbon and possibly oxygen sites. Macroscopic XANES of Co L-edge and K-edge were also measured to confirm the localized STXM result that Co3+ was partly reduced in the hybrid material. These insights should account for the superior performance of the covalently coupled Co3O4/graphene hybrid in energy related applications. © 2013 The Royal Society of Chemistry.


Martynowski D.,University of Saskatchewan | Grochulski P.,Canadian Light Source Inc. | Howard P.S.,University of Saskatchewan
Acta Crystallographica Section D: Biological Crystallography | Year: 2013

Vibrio vulnificus utilizes the type II secretion system (T2SS), culminating in a megadalton outer membrane complex called the secretin, to translocate extracellular proteins from the periplasmic space across the outer membrane. In Aeromonas hydrophila, the general secretion pathway proteins ExeA and ExeB form an inner membrane complex which interacts with peptidoglycan and is required for the assembly of the secretin composed of ExeD. In V. vulnificus, these two proteins are fused into one protein, EpsAB. Here, the crystal structure of a periplasmic domain of EpsAB (amino acids 333-584) solved by SAD phasing is presented. The crystals belonged to space group C2 and diffracted to 1.55Å resolution.


Bewer B.,Canadian Light Source Inc.
Journal of Synchrotron Radiation | Year: 2012

For X-ray absorption spectroscopy, either in transmission mode with concentrated samples or for dilute samples in fluorescence mode, it is advantageous to improve the signal-to-noise ratio by implementing a slit apparatus. Several investigations into the improvement of measurements when slits and filters are employed have been reported; however, these have always been for a particular design and are not transferable between dissimilar systems. A generalized approach to Soller slit design will be presented which enables a target level of noise rejection to be achieved by varying the number, size and placement of the filter and Soller slit assembly. A procedure for determining the reduction in efficiency of the Soller slits with respect to misalignment with the sample will also be discussed. © 2012 International Union of Crystallography Printed in Singapore - All rights reserved.


Liang Y.,Stanford University | Li Y.,Stanford University | Wang H.,Stanford University | Zhou J.,Canadian Light Source Inc. | And 3 more authors.
Nature Materials | Year: 2011

Catalysts for oxygen reduction and evolution reactions are at the heart of key renewable-energy technologies including fuel cells and water splitting. Despite tremendous efforts, developing oxygen electrode catalysts with high activity at low cost remains a great challenge. Here, we report a hybrid material consisting of Co 3O 4 nanocrystals grown on reduced graphene oxide as a high-performance bi-functional catalyst for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Although Co 3O 4 or graphene oxide alone has little catalytic activity, their hybrid exhibits an unexpected, surprisingly high ORR activity that is further enhanced by nitrogen doping of graphene. The Co 3O 4/N-doped graphene hybrid exhibits similar catalytic activity but superior stability to Pt in alkaline solutions. The same hybrid is also highly active for OER, making it a high-performance non-precious metal-based bi-catalyst for both ORR and OER. The unusual catalytic activity arises from synergetic chemical coupling effects between Co 3 O 4 and graphene. © 2011 Macmillan Publishers Limited. All rights reserved.


Patent
Canadian Light Source Inc. | Date: 2014-05-23

An apparatus for producing ^(99)Mo from a plurality of ^(100)Mo targets through a photo nuclear reaction on the ^(100)Mo targets. The apparatus comprises: (i) an electron linear accelerator component; (ii) an energy converter component capable of receiving the electron beam and producing therefrom a shower of bremsstrahlung photons; (iii) a target irradiation component for receiving the shower of bremsstrahlung photons for irradiation of a target holder mounted and positioned therein, The target holder houses a plurality of ^(100)Mo target discs. The apparatus additionally comprises (iv) a target holder transfer and recovery component for receiving, manipulating and conveying the target holder by remote control; (v) a first cooling system sealingly engaged with the energy converter component for circulation of a coolant fluid therethrough; and (vi) a second cooling system sealingly engaged with the target irradiation component for circulation of a coolant fluid therethrough.

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