INVESTIGADORES
MORENO Diego Martin
artículos
Título:
A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
Autor/es:
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.
Revista:
NATURE COMMUNICATIONS
Editorial:
Springer Nature
Referencias:
Año: 2017 vol. 8 p. 1 - 11
ISSN:
2041-1723
Resumen:
Carbapenem-resistant Enterobacteriaceae threaten human health, since carbapenems arelast resort drugs for infections by such organisms. Metallo-β-lactamases (MβLs) are the mainmechanism of resistance against carbapenems. Clinically approved inhibitors of MBLs arecurrently unavailable as design has been limited by the incomplete knowledge of theirmechanism. Here, we report a biochemical and biophysical study of carbapenem hydrolysisby the B1 enzymes NDM-1 and BcII in the bi-Zn(II) form, the mono-Zn(II) B2 Sfh-I and themono-Zn(II) B3 GOB-18. These MβLs hydrolyse carbapenems via a similar mechanism, withaccumulation of the same anionic intermediates. We characterize the Michaelis complexformed by mono-Zn(II) enzymes, and we identify all intermediate species, enabling us topropose a chemical mechanism for mono and binuclear MβLs. This common mechanismopen avenues for rationally designed inhibitors of all MβLs, notwithstanding the profounddifferences between these enzymes? active site structure, β-lactam specificity and metalcontent