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

ABSTRACT: ?-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 ?-lactamases also degrade clinically used 1?-methyl-substituted carbapenems through the unprecedented formation of a carbapenem-derived ?-lactone. ?-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 ?-lactamases (particularly class?D) and metallo-?-lactamases. These results define a new mechanism for the class?D carbapenemases, in which a hydrolytic water molecule is not required.

SUBMITTER: Lohans CT

PROVIDER: S-EPMC5817396 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Lohans Christopher T CT van Groesen Emma E Kumar Kiran K Tooke Catherine L CL Spencer James J Paton Robert S RS Brem Jürgen J Schofield Christopher J CJ

Angewandte Chemie (International ed. in English) 20180105 5

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 ca ...[more]

PMID: 29236332

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