6d1f: Difference between revisions
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==Crystal structure of NDM-1 complexed with compound 8== | |||
<StructureSection load='6d1f' size='340' side='right'caption='[[6d1f]], [[Resolution|resolution]] 1.15Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6d1f]] is a 1 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=6D1F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D1F 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]] 1.15Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=P9T:[(5,7-difluoro-2-oxo-2H-1-benzopyran-4-yl)methyl]phosphonic+acid'>P9T</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6d1f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d1f OCA], [https://pdbe.org/6d1f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d1f RCSB], [https://www.ebi.ac.uk/pdbsum/6d1f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d1f ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BLAN1_KLEPN BLAN1_KLEPN] Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Gram-negative pathogens expressing serine beta-lactamases (SBLs) and metallo-beta-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all beta-lactam antibiotics. Here we describe the discovery of a heteroaryl phosphonate scaffold that exhibits noncovalent cross-class inhibition of representative carbapenemases, specifically the SBL KPC-2 and the MBLs NDM-1 and VIM-2. The most potent lead, compound 16, exhibited low nM to low muM inhibition of KPC-2, NDM-1, and VIM-2. Compound 16 potentiated imipenem efficacy against resistant clinical and laboratory bacterial strains expressing carbapenemases while showing some cytotoxicity toward human HEK293T cells only at concentrations above 100 mug/mL. Complex structures with KPC-2, NDM-1, and VIM-2 demonstrate how these inhibitors achieve high binding affinity to both enzyme classes. These findings provide a structurally and mechanistically new scaffold for drug discovery targeting multidrug resistant Gram-negative pathogens and more generally highlight the active site features of carbapenemases that can be leveraged for lead discovery. | |||
Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases.,Pemberton OA, Jaishankar P, Akhtar A, Adams JL, Shaw LN, Renslo AR, Chen Y J Med Chem. 2019 Sep 26;62(18):8480-8496. doi: 10.1021/acs.jmedchem.9b00728. Epub, 2019 Sep 13. PMID:31483651<ref>PMID:31483651</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6d1f" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Klebsiella pneumoniae]] | |||
[[Category: Large Structures]] | |||
[[Category: Chen Y]] | |||
[[Category: Pemberton OA]] | |||
Latest revision as of 18:15, 4 October 2023
Crystal structure of NDM-1 complexed with compound 8Crystal structure of NDM-1 complexed with compound 8
Structural highlights
FunctionBLAN1_KLEPN Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin. Publication Abstract from PubMedGram-negative pathogens expressing serine beta-lactamases (SBLs) and metallo-beta-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all beta-lactam antibiotics. Here we describe the discovery of a heteroaryl phosphonate scaffold that exhibits noncovalent cross-class inhibition of representative carbapenemases, specifically the SBL KPC-2 and the MBLs NDM-1 and VIM-2. The most potent lead, compound 16, exhibited low nM to low muM inhibition of KPC-2, NDM-1, and VIM-2. Compound 16 potentiated imipenem efficacy against resistant clinical and laboratory bacterial strains expressing carbapenemases while showing some cytotoxicity toward human HEK293T cells only at concentrations above 100 mug/mL. Complex structures with KPC-2, NDM-1, and VIM-2 demonstrate how these inhibitors achieve high binding affinity to both enzyme classes. These findings provide a structurally and mechanistically new scaffold for drug discovery targeting multidrug resistant Gram-negative pathogens and more generally highlight the active site features of carbapenemases that can be leveraged for lead discovery. Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases.,Pemberton OA, Jaishankar P, Akhtar A, Adams JL, Shaw LN, Renslo AR, Chen Y J Med Chem. 2019 Sep 26;62(18):8480-8496. doi: 10.1021/acs.jmedchem.9b00728. Epub, 2019 Sep 13. PMID:31483651[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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