6QWB

Crystal structure of KPC-4 complexed with relebactam (16 hour soak)

Summary for 6QWB

• Entry DOI: 10.2210/pdb6qwb/pdb
• Descriptor: Beta-lactamase, SULFATE ION, (2~{S})-5-azanylidene-2-(piperidin-4-ylcarbamoyl)piperidine-1-carboxylic acid, ... (6 entities in total)
• Functional Keywords: inhibitor, relebactam, diazabicyclooctane, antibiotic resistance., antimicrobial protein
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 31919.68

Authors

Tooke, C.L.,Hinchliffe, P.,Spencer, J. (deposition date: 2019-03-05, release date: 2019-08-21, Last modification date: 2024-01-24)

Primary citation

Tooke, C.L.,Hinchliffe, P.,Lang, P.A.,Mulholland, A.J.,Brem, J.,Schofield, C.J.,Spencer, J.
Molecular Basis of Class A beta-Lactamase Inhibition by Relebactam.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: β-Lactamase production is the major β-lactam resistance mechanism in Gram-negative bacteria. β-Lactamase inhibitors (BLIs) efficacious against serine β-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 the treatment of infections by multidrug-resistant 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 β-lactamases L2 (inhibition constant 3 μM) and CTX-M-15 (21 μM) and the carbapenemases KPC-2, -3, and -4 (1 to 5 μM). Against purified class A SBLs, relebactam is an inferior inhibitor compared with the clinically approved DBO avibactam (9- to 120-fold differences in half maximal inhibitory concentration [IC]). MIC assays indicate relebactam potentiates β-lactam (imipenem) activity against KPC-producing , with similar potency to avibactam (with ceftazidime). Relebactam is less effective than avibactam in combination with aztreonam against 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 than that of 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-β-lactam combinations.

PubMed: 31383664
DOI: 10.1128/AAC.00564-19

Experimental method

X-RAY DIFFRACTION (1.04 Å)