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

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...

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Autores principales: Lisa, María Natalia, Palacios, Antonela R., Aitha, Mahesh, González, Mariano M., Moreno, Diego M., Crowder, Michael W., Bonomo, Robert A., Spencer, James, Tierney, David L., Llarrull, Leticia I., Vila, Alejandro J.
Formato: article artículo publishedVersion
Lenguaje:Inglés
Publicado: Nature 2021
Materias:
Metallo-beta-lactamases
Carbapenems
Reaction Mechanism
Acceso en línea:http://hdl.handle.net/2133/20014
http://hdl.handle.net/2133/20014
Aporte de:
Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR) de Universidad Nacional de Rosario
id I15-R121-2133-20014
record_format dspace
institution Universidad Nacional de Rosario
institution_str I-15
repository_str R-121
collection Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR)
language Inglés
orig_language_str_mv eng
topic Metallo-beta-lactamases
Carbapenems
Reaction Mechanism
spellingShingle Metallo-beta-lactamases
Carbapenems
Reaction Mechanism
Lisa, María Natalia
Palacios, Antonela R.
Aitha, Mahesh
González, Mariano M.
Moreno, Diego M.
Crowder, Michael W.
Bonomo, Robert A.
Spencer, James
Tierney, David L.
Llarrull, Leticia I.
Vila, Alejandro J.
A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
topic_facet Metallo-beta-lactamases
Carbapenems
Reaction Mechanism
description 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.
format article
artículo
publishedVersion
author Lisa, María Natalia
Palacios, Antonela R.
Aitha, Mahesh
González, Mariano M.
Moreno, Diego M.
Crowder, Michael W.
Bonomo, Robert A.
Spencer, James
Tierney, David L.
Llarrull, Leticia I.
Vila, Alejandro J.
author_facet Lisa, María Natalia
Palacios, Antonela R.
Aitha, Mahesh
González, Mariano M.
Moreno, Diego M.
Crowder, Michael W.
Bonomo, Robert A.
Spencer, James
Tierney, David L.
Llarrull, Leticia I.
Vila, Alejandro J.
author_sort Lisa, María Natalia
title A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
title_short A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
title_full A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
title_fullStr A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
title_full_unstemmed A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
title_sort general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
publisher Nature
publishDate 2021
url http://hdl.handle.net/2133/20014
http://hdl.handle.net/2133/20014
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