Molecular Basis of Class A β-Lactamase Inhibition by Relebactam

Antimicrobial Agents and Chemotherapy
Catherine L TookeJames Spencer

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. ...Continue Reading

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Citations

Mar 3, 2020·Chemical & Pharmaceutical Bulletin·Yasunari Otsuka
Dec 4, 2020·Infection and Drug Resistance·Toni A Campanella, Jason C Gallagher
Nov 18, 2020·Antimicrobial Agents and Chemotherapy·Pauline A LangJürgen Brem
Feb 4, 2021·The Journal of Antimicrobial Chemotherapy·Ursula TheuretzbacherEvelina Tacconelli
Dec 10, 2020·International Journal of Molecular Sciences·Juan C Vázquez-UchaAlejandro Beceiro
Nov 13, 2020·Clinical Microbiology Reviews·Dafna YahavLeonard Leibovici
Jan 23, 2021·RSC Medicinal Chemistry·Catherine L TookeJames Spencer
Jul 21, 2020·Pharmacotherapy·Hannah K SpencerSamuel L Aitken
Feb 23, 2021·European Journal of Medicinal Chemistry·Anka LucicChristopher J Schofield
Jul 14, 2021·Clinical Pharmacokinetics·Matthew William McCarthy
Jul 24, 2021·Nature Communications·Agata ButrynAllen M Orville
Aug 3, 2021·Antimicrobial Agents and Chemotherapy·Alessandra CarattoliGiammarco Raponi
Oct 5, 2021·Antimicrobial Agents and Chemotherapy·Agnès B JoussetThierry Naas

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Clinical Trials Mentioned

NCT02452047

Software Mentioned

phenix
CCP4 suite
WinCoot
CCP4
Phaser
eLBOW
Xia2
Refmac
GraphPad Prism
refine

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