A New Mechanism for β-Lactamases: Class D Enzymes Degrade 1β-Methyl Carbapenems through Lactone Formation

Christopher T. Lohans, Emma van Groesen, Kiran Kumar, Catherine L. Tooke, James Spencer, Robert S. Paton, Jürgen Brem, Christopher J. Schofield*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

6 Citations (Scopus)
173 Downloads (Pure)

Abstract

β-Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl-enzyme intermediate. We show that class D β-lactamases also degrade clinically used 1β-methyl-substituted carbapenems through the unprecedented formation of a carbapenem-derived β-lactone. β-Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl-enzyme intermediate. The carbapenem-derived lactone products inhibit both serine β-lactamases (particularly class D) and metallo-β-lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required.
Original languageEnglish
Pages (from-to)1282-1285
Number of pages4
JournalAngewandte Chemie - International Edition
Volume57
Issue number5
Early online date5 Jan 2018
DOIs
Publication statusPublished - Jan 2018

Keywords

  • antibiotics
  • carbapenems
  • hydrolases
  • lactones
  • β-lactamases

Fingerprint Dive into the research topics of 'A New Mechanism for β-Lactamases: Class D Enzymes Degrade 1β-Methyl Carbapenems through Lactone Formation'. Together they form a unique fingerprint.

  • Cite this