4x68: Difference between revisions
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<StructureSection load='4x68' size='340' side='right'caption='[[4x68]], [[Resolution|resolution]] 1.68Å' scene=''> | <StructureSection load='4x68' size='340' side='right'caption='[[4x68]], [[Resolution|resolution]] 1.68Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4x68]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4x68]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X68 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X68 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=OP0:(2S,5R)-N-(2-AMINOETHOXY)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>OP0</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=OP0:(2S,5R)-N-(2-AMINOETHOXY)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>OP0</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=4x68 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x68 OCA], [https://pdbe.org/4x68 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x68 RCSB], [https://www.ebi.ac.uk/pdbsum/4x68 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x68 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/AMPC_PSEAE AMPC_PSEAE] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Pseudomonas aeruginosa PAO1]] | ||
[[Category: Watanabe | [[Category: Watanabe T]] | ||
[[Category: Yamada | [[Category: Yamada M]] | ||
Revision as of 00:15, 13 April 2023
Crystal Structure of OP0595 complexed with AmpCCrystal Structure of OP0595 complexed with AmpC
Structural highlights
FunctionPublication Abstract from PubMedOBJECTIVES: The production of a growing diversity of beta-lactamases by Gram-negative bacteria challenges antimicrobial chemotherapy. OP0595, discovered separately by each of Meiji Seika Pharma and Fedora Pharmaceuticals, is a new diazabicyclooctane serine beta-lactamase inhibitor that also acts as an antibiotic and as a beta-lactamase-independent beta-lactam 'enhancer'. METHODS: Inhibitory activity against serine beta-lactamases and affinity for PBPs were determined using nitrocefin and Bocillin FL, respectively. MICs alone and in combination with beta-lactam agents were measured according to CLSI recommendations. Morphological changes in Escherichia coli were examined by phase-contrast microscopy. RESULTS: IC50s of OP0595 for class A and C beta-lactamases were <1000 nM, with covalent binding demonstrated to the active-site serine of CTX-M-44 and AmpC enzymes. OP0595 also had direct antibiotic activity against many Enterobacteriaceae, associated with inhibition of PBP2 and conversion of the bacteria into spherical forms. Synergy between OP0595 and beta-lactam agents was seen against strains producing class A and C beta-lactamases vulnerable to inhibition. Lastly, OP0595 lowered the MICs of PBP3-targeted partner beta-lactam agents for a non-beta-lactamase-producing E. coli mutant that was resistant to OP0595 itself, indicating beta-lactamase-independent 'enhancer'-based synergy. CONCLUSIONS: OP0595 acts in three ways: (i) as an inhibitor of class A and C beta-lactamases, covalently binding at their active sites; (ii) as an antibacterial, by inhibiting PBP2 of several Enterobacteriaceae; and (iii) as an 'enhancer' of beta-lactam agents that bind to other PBPs besides PBP2 for several Enterobacteriaceae. OP0595 has considerable potential to overcome resistance when it is combined with various beta-lactam agents. OP0595, a new diazabicyclooctane: mode of action as a serine beta-lactamase inhibitor, antibiotic and beta-lactam 'enhancer'.,Morinaka A, Tsutsumi Y, Yamada M, Suzuki K, Watanabe T, Abe T, Furuuchi T, Inamura S, Sakamaki Y, Mitsuhashi N, Ida T, Livermore DM J Antimicrob Chemother. 2015 Jun 18. pii: dkv166. PMID:26089439[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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