A new mechanism for β-lactamases: Class D enzymes degrade 1β-methyl carbapenems through lactone formation

Journal article

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.

Authors: Lohans, C; van Groesen, E; Kumar, K; Tooke, C; Spencer, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Angewandte Chemie International Edition
• Volume: 57
• Issue: 5
• Pages: 1282-1285
• Publication date: 2018-01-05
• Acceptance date: 2017-12-13
• DOI: 10.1002/anie.201711308
• EISSN: 1521-3773
• ISSN: 1433-7851
• Pmid: 29236332
• Language: English
• Keywords: antibiotics; lactones; carbapenems; β-lactamases; hydrolases