5fas: Difference between revisions
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==OXA-48 in complex with FPI-1523== | |||
<StructureSection load='5fas' size='340' side='right'caption='[[5fas]], [[Resolution|resolution]] 1.74Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5fas]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FAS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FAS FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.74Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5VR:[[(3~{R},6~{S})-6-(ACETAMIDOCARBAMOYL)-1-METHANOYL-PIPERIDIN-3-YL]AMINO]+HYDROGEN+SULFATE'>5VR</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5fas FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fas OCA], [https://pdbe.org/5fas PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fas RCSB], [https://www.ebi.ac.uk/pdbsum/5fas PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fas ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q6XEC0_KLEPN Q6XEC0_KLEPN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Avibactam is a diazabicyclooctane beta-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with beta-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important beta-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC </= 2 mug/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both beta-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens. | |||
Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-beta-Lactamases and Penicillin-Binding Proteins.,King AM, King DT, French S, Brouillette E, Asli A, Alexander JA, Vuckovic M, Maiti SN, Parr TR Jr, Brown ED, Malouin F, Strynadka NC, Wright GD ACS Chem Biol. 2016 Jan 14. PMID:26731698<ref>PMID:26731698</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5fas" style="background-color:#fffaf0;"></div> | ||
[[Category: Asli | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Klebsiella pneumoniae]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Alexander AN]] | ||
[[Category: | [[Category: Asli A]] | ||
[[Category: | [[Category: Brouillette E]] | ||
[[Category: Brown ED]] | |||
[[Category: French S]] | |||
[[Category: King AM]] | |||
[[Category: King DT]] | |||
[[Category: Maiti SN]] | |||
[[Category: Malouin F]] | |||
[[Category: Parr TR]] | |||
[[Category: Strynadka NCJ]] | |||
[[Category: Vuckovic M]] | |||
[[Category: Wright GD]] | |||
Latest revision as of 09:44, 19 July 2023
OXA-48 in complex with FPI-1523OXA-48 in complex with FPI-1523
Structural highlights
FunctionPublication Abstract from PubMedAvibactam is a diazabicyclooctane beta-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with beta-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important beta-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC </= 2 mug/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both beta-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens. Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-beta-Lactamases and Penicillin-Binding Proteins.,King AM, King DT, French S, Brouillette E, Asli A, Alexander JA, Vuckovic M, Maiti SN, Parr TR Jr, Brown ED, Malouin F, Strynadka NC, Wright GD ACS Chem Biol. 2016 Jan 14. PMID:26731698[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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