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

María-Natalia Lisa, Antonela R. Palacios, Mahesh Aitha, Mariano M. González, Diego M. Moreno, Michael W. Crowder, Robert A. Bonomo, James Spencer, David L. Tierney, Leticia I. Llarrull () and Alejandro J. Vila ()
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María-Natalia Lisa: Ocampo y Esmeralda
Antonela R. Palacios: Ocampo y Esmeralda
Mahesh Aitha: Miami University
Mariano M. González: Ocampo y Esmeralda
Diego M. Moreno: Instituto de Química Rosario (IQUIR, CONICET-UNR)
Michael W. Crowder: Miami University
Robert A. Bonomo: Louis Stokes Cleveland Department of Veterans Affairs Medical Center
James Spencer: University of Bristol Biomedical Sciences Building, University Walk
David L. Tierney: Miami University
Leticia I. Llarrull: Ocampo y Esmeralda
Alejandro J. Vila: Ocampo y Esmeralda

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Carbapenem-resistant Enterobacteriaceae threaten human health, since carbapenems are last resort drugs for infections by such organisms. Metallo-β-lactamases (MβLs) 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 MβLs 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 MβLs. This common mechanism open avenues for rationally designed inhibitors of all MβLs, notwithstanding the profound differences between these enzymes’ active site structure, β-lactam specificity and metal content.

Date: 2017
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DOI: 10.1038/s41467-017-00601-9

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