A New Mechanism for β-Lactamases: Class D Enzymes Degrade 1β-Methyl Carbapenems through Lactone Formation
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.
Lohans, Christopher T.,van Groesen, Emma,Kumar, Kiran,Tooke, Catherine L.,Spencer, James,Paton, Robert S.,Brem, Jürgen,Schofield, Christopher J.
The present invention relates to certain β-lactone compounds that may be useful as inhibitors of bacterial beta-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising t
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Paragraph 00161-00162; 00159-00160
(2019/06/23)
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