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Molecular Basis of Class A β-Lactamase Inhibition by Relebactam.
Antimicrob Agents Chemother. 2019 10; 63(10)AA

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 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 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 [IC50]). MIC assays indicate relebactam potentiates β-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 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.

Authors+Show Affiliations

School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, United Kingdom.School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, United Kingdom.Department of Chemistry, University of Oxford, Oxford, United Kingdom.Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, United Kingdom.Department of Chemistry, University of Oxford, Oxford, United Kingdom.Department of Chemistry, University of Oxford, Oxford, United Kingdom.School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, United Kingdom Jim.Spencer@bristol.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

31383664

Citation

Tooke, Catherine L., et al. "Molecular Basis of Class a β-Lactamase Inhibition By Relebactam." Antimicrobial Agents and Chemotherapy, vol. 63, no. 10, 2019.
Tooke CL, Hinchliffe P, Lang PA, et al. Molecular Basis of Class A β-Lactamase Inhibition by Relebactam. Antimicrob Agents Chemother. 2019;63(10).
Tooke, C. L., Hinchliffe, P., Lang, P. A., Mulholland, A. J., Brem, J., Schofield, C. J., & Spencer, J. (2019). Molecular Basis of Class A β-Lactamase Inhibition by Relebactam. Antimicrobial Agents and Chemotherapy, 63(10). https://doi.org/10.1128/AAC.00564-19
Tooke CL, et al. Molecular Basis of Class a β-Lactamase Inhibition By Relebactam. Antimicrob Agents Chemother. 2019;63(10) PubMed PMID: 31383664.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular Basis of Class A β-Lactamase Inhibition by Relebactam. AU - Tooke,Catherine L, AU - Hinchliffe,Philip, AU - Lang,Pauline A, AU - Mulholland,Adrian J, AU - Brem,Jürgen, AU - Schofield,Christopher J, AU - Spencer,James, Y1 - 2019/09/23/ PY - 2019/03/14/received PY - 2019/07/04/accepted PY - 2019/8/7/pubmed PY - 2020/8/4/medline PY - 2019/8/7/entrez KW - antibiotic resistance KW - avibactam KW - diazabicyclooctane KW - relebactam KW - serine β-lactamase inhibitors JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 63 IS - 10 N2 - 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 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 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 [IC50]). MIC assays indicate relebactam potentiates β-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 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/31383664/Molecular_Basis_of_Class_A_β_Lactamase_Inhibition_by_Relebactam_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=31383664 DB - PRIME DP - Unbound Medicine ER -