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==Crystal structure of KPC-4 complexed with relebactam (1 hour soak)== | |||
<StructureSection load='6qwc' size='340' side='right'caption='[[6qwc]], [[Resolution|resolution]] 1.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6qwc]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QWC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QWC FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MK7:(2S,5R)-1-FORMYL-N-(PIPERIDIN-4-YL)-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>MK7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6qwc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qwc OCA], [http://pdbe.org/6qwc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qwc RCSB], [http://www.ebi.ac.uk/pdbsum/6qwc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qwc ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
beta-Lactamase production is the major beta-lactam resistance mechanism in Gram-negative bacteria. beta-Lactamase inhibitors (BLIs) efficacious against serine beta-lactamase (SBL) producers, especially strains carrying the widely disseminated class A enzymes, are required. Relebactam, a diazabicyclooctane (DBO) BLI is in phase-3 clinical trials in combination with imipenem, for treatment of infections by multi-drug resistant Enterobacteriaceae. We show that relebactam inhibits five clinically-important class A SBLs (despite their differing spectra of activity), representing both chromosomal and plasmid-borne enzymes, i.e. the extended spectrum beta-lactamases L2 (inhibition constant 3 muM) and CTX-M-15 (21 muM); and the carbapenemases, KPC-2, -3 and -4 (1 - 5 muM). Against purified class A SBLs, relebactam is an inferior inhibitor compared to the clinically approved DBO avibactam, (9 to 120-fold differences in IC50). Minimum inhibitory concentration assays indicate relebactam potentiates beta-lactam (imipenem) activity against KPC-producing Klebsiella pneumoniae with similar potency to avibactam (with ceftazidime). Relebactam is less effective than avibactam in combination with aztreonam against Stenotrophomonas maltophilia K279a. X-ray crystal structures of relebactam bound to CTX-M-15, L2, KPC-2, KPC-3 and KPC-4 reveal its C2 linked piperidine ring can sterically clash with Asn104 (CTX-M-15) or His/Trp105 (L2 and KPCs), rationalizing its poorer inhibition activity compared to avibactam, which has a smaller C2 carboxyamide group. Mass spectrometry and crystallographic data show slow, pH-dependent relebactam desulfation by KPC-2, -3 and -4. This comprehensive comparison of relebactam binding across five clinically-important class A SBLs will inform the design of future DBOs with the aim of improving clinical efficacy of BLI:beta-lactam combinations. | |||
Molecular Basis of Class A beta-lactamase Inhibition by Relebactam.,Tooke CL, Hinchliffe P, Lang PA, Mulholland AJ, Brem J, Schofield CJ, Spencer J Antimicrob Agents Chemother. 2019 Aug 5. pii: AAC.00564-19. doi:, 10.1128/AAC.00564-19. PMID:31383664<ref>PMID:31383664</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6qwc" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Beta-lactamase]] | |||
[[Category: Large Structures]] | |||
[[Category: Hinchliffe, P]] | |||
[[Category: Spencer, J]] | |||
[[Category: Tooke, C L]] | |||
[[Category: Antibiotic resistance]] | |||
[[Category: Antimicrobial protein]] | |||
[[Category: Diazabicyclooctane]] | |||
[[Category: Inhibitor]] | |||
[[Category: Relebactam]] | |||
Revision as of 09:10, 21 August 2019
Crystal structure of KPC-4 complexed with relebactam (1 hour soak)Crystal structure of KPC-4 complexed with relebactam (1 hour soak)
Structural highlights
Publication Abstract from PubMedbeta-Lactamase production is the major beta-lactam resistance mechanism in Gram-negative bacteria. beta-Lactamase inhibitors (BLIs) efficacious against serine beta-lactamase (SBL) producers, especially strains carrying the widely disseminated class A enzymes, are required. Relebactam, a diazabicyclooctane (DBO) BLI is in phase-3 clinical trials in combination with imipenem, for treatment of infections by multi-drug resistant Enterobacteriaceae. We show that relebactam inhibits five clinically-important class A SBLs (despite their differing spectra of activity), representing both chromosomal and plasmid-borne enzymes, i.e. the extended spectrum beta-lactamases L2 (inhibition constant 3 muM) and CTX-M-15 (21 muM); and the carbapenemases, KPC-2, -3 and -4 (1 - 5 muM). Against purified class A SBLs, relebactam is an inferior inhibitor compared to the clinically approved DBO avibactam, (9 to 120-fold differences in IC50). Minimum inhibitory concentration assays indicate relebactam potentiates beta-lactam (imipenem) activity against KPC-producing Klebsiella pneumoniae with similar potency to avibactam (with ceftazidime). Relebactam is less effective than avibactam in combination with aztreonam against Stenotrophomonas maltophilia K279a. X-ray crystal structures of relebactam bound to CTX-M-15, L2, KPC-2, KPC-3 and KPC-4 reveal its C2 linked piperidine ring can sterically clash with Asn104 (CTX-M-15) or His/Trp105 (L2 and KPCs), rationalizing its poorer inhibition activity compared to avibactam, which has a smaller C2 carboxyamide group. Mass spectrometry and crystallographic data show slow, pH-dependent relebactam desulfation by KPC-2, -3 and -4. This comprehensive comparison of relebactam binding across five clinically-important class A SBLs will inform the design of future DBOs with the aim of improving clinical efficacy of BLI:beta-lactam combinations. Molecular Basis of Class A beta-lactamase Inhibition by Relebactam.,Tooke CL, Hinchliffe P, Lang PA, Mulholland AJ, Brem J, Schofield CJ, Spencer J Antimicrob Agents Chemother. 2019 Aug 5. pii: AAC.00564-19. doi:, 10.1128/AAC.00564-19. PMID:31383664[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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