3 research outputs found
A New Mechanism for βâLactamases: Class D Enzymes Degrade 1βâMethyl Carbapenems through Lactone Formation
βâLactamases 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 acylâenzyme intermediate. We show that classâ
D βâlactamases also degrade clinically used 1βâmethylâsubstituted carbapenems through the unprecedented formation of a carbapenemâderived βâlactone. βâLactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acylâenzyme intermediate. The carbapenemâderived lactone products inhibit both serine βâlactamases (particularly classâ
D) and metalloâβâlactamases. These results define a new mechanism for the classâ
D carbapenemases, in which a hydrolytic water molecule is not required.FWN â Publicaties zonder aanstelling Universiteit Leide
A New Mechanism for βâLactamases: Class D Enzymes Degrade 1βâMethyl Carbapenems through Lactone Formation
βâLactamases 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 acylâenzyme intermediate. We show that classâ
D βâlactamases also degrade clinically used 1βâmethylâsubstituted carbapenems through the unprecedented formation of a carbapenemâderived βâlactone. βâLactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acylâenzyme intermediate. The carbapenemâderived lactone products inhibit both serine βâlactamases (particularly classâ
D) and metalloâβâlactamases. These results define a new mechanism for the classâ
D carbapenemases, in which a hydrolytic water molecule is not required.FWN â Publicaties zonder aanstelling Universiteit Leide