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==Crystal structure KPC-2 beta-lactamase complexed with WCK 5107 by soaking== | |||
<StructureSection load='6b1j' size='340' side='right' caption='[[6b1j]], [[Resolution|resolution]] 1.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6b1j]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B1J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B1J FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C8V:(2S,5R)-1-formyl-N-[(3R)-piperidine-3-carbonyl]-5-[(sulfooxy)amino]piperidine-2-carbohydrazide'>C8V</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6b1f|6b1f]]</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=6b1j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b1j OCA], [http://pdbe.org/6b1j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b1j RCSB], [http://www.ebi.ac.uk/pdbsum/6b1j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b1j ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/BLKPC_KLEPN BLKPC_KLEPN]] Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum beta-lactamases. The design of novel beta-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C, and D beta-lactamases with unprecedented k2/ K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C beta-lactamses rapidly but not the tested OXAs. Compounds 1-3 formed highly stable acyl-complexes as demonstrated by mass spectrometry. Crystallography revealed that 1-3 complexed with KPC-2 adopted a "chair conformation" with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were effective in murine peritonitis and neutropenic lung infection models caused by MDR Acinetobacter baumannii. Compounds 1-3 are novel beta-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted. | |||
Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using beta-Lactamase Inhibitors and beta-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234.,Papp-Wallace KM, Nguyen NQ, Jacobs MR, Bethel CR, Barnes MD, Kumar V, Bajaksouzian S, Rudin SD, Rather PN, Bhavsar S, Ravikumar T, Deshpande PK, Patil V, Yeole R, Bhagwat SS, Patel MV, van den Akker F, Bonomo RA J Med Chem. 2018 May 10;61(9):4067-4086. doi: 10.1021/acs.jmedchem.8b00091. Epub , 2018 Apr 20. PMID:29627985<ref>PMID:29627985</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6b1j" style="background-color:#fffaf0;"></div> | ||
[[Category: Nguyen, N | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Beta-lactamase]] | |||
[[Category: Akker, F van den]] | |||
[[Category: Nguyen, N Q]] | |||
[[Category: Complex]] | |||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Inhibitor]] | |||
Revision as of 21:42, 1 August 2018
Crystal structure KPC-2 beta-lactamase complexed with WCK 5107 by soakingCrystal structure KPC-2 beta-lactamase complexed with WCK 5107 by soaking
Structural highlights
Function[BLKPC_KLEPN] Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency. Publication Abstract from PubMedLimited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum beta-lactamases. The design of novel beta-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C, and D beta-lactamases with unprecedented k2/ K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C beta-lactamses rapidly but not the tested OXAs. Compounds 1-3 formed highly stable acyl-complexes as demonstrated by mass spectrometry. Crystallography revealed that 1-3 complexed with KPC-2 adopted a "chair conformation" with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were effective in murine peritonitis and neutropenic lung infection models caused by MDR Acinetobacter baumannii. Compounds 1-3 are novel beta-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted. Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using beta-Lactamase Inhibitors and beta-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234.,Papp-Wallace KM, Nguyen NQ, Jacobs MR, Bethel CR, Barnes MD, Kumar V, Bajaksouzian S, Rudin SD, Rather PN, Bhavsar S, Ravikumar T, Deshpande PK, Patil V, Yeole R, Bhagwat SS, Patel MV, van den Akker F, Bonomo RA J Med Chem. 2018 May 10;61(9):4067-4086. doi: 10.1021/acs.jmedchem.8b00091. Epub , 2018 Apr 20. PMID:29627985[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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