A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-?-lactamases.

ABSTRACT: Carbapenem-resistant Enterobacteriaceae threaten human health, since carbapenems are last resort drugs for infections by such organisms. Metallo-?-lactamases (M?Ls) are the main mechanism of resistance against carbapenems. Clinically approved inhibitors of MBLs are currently unavailable as design has been limited by the incomplete knowledge of their mechanism. Here, we report a biochemical and biophysical study of carbapenem hydrolysis by the B1 enzymes NDM-1 and BcII in the bi-Zn(II) form, the mono-Zn(II) B2 Sfh-I and the mono-Zn(II) B3 GOB-18. These M?Ls hydrolyse carbapenems via a similar mechanism, with accumulation of the same anionic intermediates. We characterize the Michaelis complex formed by mono-Zn(II) enzymes, and we identify all intermediate species, enabling us to propose a chemical mechanism for mono and binuclear M?Ls. This common mechanism open avenues for rationally designed inhibitors of all M?Ls, notwithstanding the profound differences between these enzymes' active site structure, ?-lactam specificity and metal content.Carbapenem-resistant bacteria pose a major health threat by expressing metallo-?-lactamases (M?Ls), enzymes able to hydrolyse these life-saving drugs. Here the authors use biophysical and computational methods and show that different M?Ls share the same reaction mechanism, suggesting new strategies for drug design.

SUBMITTER: Lisa MN 

PROVIDER: S-EPMC5599593 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature