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

摘要

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