A new mechanism for β-lactamases: Class D enzymes degrade 1β-methyl carbapenems through lactone formation
| Autor: | Christopher T. Lohans, Emma van Groesen, Kiran Kumar, Catherine L. Tooke, James Spencer, Robert S. Paton, Jürgen Brem, Christopher J. Schofield |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Communication 030106 microbiology β-lactamases hydrolases General Medicine biochemical phenomena metabolism and nutrition bacterial infections and mycoses Communications antibiotics lactones 3. Good health 03 medical and health sciences 030104 developmental biology Antibiotic Resistance polycyclic compounds bacteria carbapenems |
| Zdroj: | Angewandte Chemie International Edition, 130(5), 1296-1299 Lohans, C T, van Groesen, E, Kumar, K, Tooke, C L, Spencer, J, Paton, R S, Brem, J & Schofield, C J 2018, ' A New Mechanism for β-Lactamases : Class D Enzymes Degrade 1β-Methyl Carbapenems through Lactone Formation ', Angewandte Chemie-International Edition, vol. 57, no. 5, pp. 1282-1285 . https://doi.org/10.1002/anie.201711308 Angewandte Chemie (International Ed. in English) |
| ISSN: | 1296-1299 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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