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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)1282-1285
Number of pages4
JournalAngewandte Chemie - International Edition
Volume57
Issue number5
Early online date5 Jan 2018
DOIs
DateAccepted/In press - 13 Dec 2017
DateE-pub ahead of print - 5 Jan 2018
DatePublished (current) - Jan 2018

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.

    Research areas

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

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Wiley at https://doi.org/10.1002/anie.201711308 . Please refer to any applicable terms of use of the publisher.

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