Inhibitors of Metallo-β-lactamase Generated from β-lactam Antibiotics

Adriana Badarau, Antonio Llińa, Andrew P. Laws, Christian Damblon, Michael I. Page

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The resistance of bacteria to the normally lethal action of β-lactam antibiotics is largely due to the production of β-lactamases that catalyze the hydrolysis of the β-lactam. One class of these enzymes is a zinc-dependent metallo-β-lactamase for which there are no clinically available inhibitors. The hydrolysis of cephalosporin β-lactam antibiotics generates dihydrothiazines which subsequently undergo isomerization at C6 by C-S bond cleavage and through the intermediacy of a thiol. These thiols can be trapped by the β-lactamase from Bacillus cereus, causing inhibition of the enzyme. The rate of production of the thiol corresponds to the rate of inhibition, and the inhibition constants are in the micromolar range but vary with the nature of the cephalosporin derivative. NMR studies have identified the structure of the thiols causing inhibition and also show that the thiol binds to the zinc ion, which in turn perturbs the metal-bound histidines. Inhibition is slowly removed as the thiol becomes oxidized or undergoes further degradation. The thiol intermediate generated from cephalothin is a slow binding inhibitor. There is no observed inhibition from the analogous degradation products from penicillins.

Original languageEnglish
Pages (from-to)8578-8589
Number of pages12
JournalBiochemistry
Volume44
Issue number24
Early online date27 May 2005
DOIs
Publication statusPublished - 21 Jun 2005

Fingerprint Dive into the research topics of 'Inhibitors of Metallo-β-lactamase Generated from β-lactam Antibiotics'. Together they form a unique fingerprint.

  • Cite this