4x69: Difference between revisions
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4x68|4x68]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4x68|4x68]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4x69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x69 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4x69 RCSB], [http://www.ebi.ac.uk/pdbsum/4x69 PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4x69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x69 OCA], [http://pdbe.org/4x69 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x69 RCSB], [http://www.ebi.ac.uk/pdbsum/4x69 PDBsum]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4x69" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 00:49, 16 October 2015
Crystal structure of OP0595 complexed with CTX-M-44Crystal structure of OP0595 complexed with CTX-M-44
Structural highlights
Function[BLT1_ECOLX] Has strong cefotaxime-hydrolyzing activity. Publication 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. References
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