IBR   13079
INSTITUTO DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Fine tuning of the catalytic efficiency and metal binding features in metalloenzymes by Outer Sphere residues
Autor/es:
VILA, ALEJANDRO JOSÉ
Lugar:
Boston
Reunión:
Conferencia; ACS; 2015
Institución organizadora:
ACS
Resumen:
The beta-lactam antibiotic family representsthe largest group of commercial antibiotics clinically used to treatGram-negative and Gram-positive infections. The synthesis of beta-lactamases isthe most widely spread resistance mechanisms displayed by bacteria. beta-Lactamases are hydrolytic enzymes thatselectively cleave the four-membered beta-lactam ring, rendering antibioticsineffective against their natural targets. There are four molecular classes ofbeta-lactamases known so far, namely, A-D, and include both metal-dependent(class B) and enzymes with a serine in the active site (classes A, C, and D).Metallo-Beta-Lactamases (MBLs) are divided into three subclasses, B1, B2, andB3, all exhibiting resistance to commercially available beta-lactamase inhibitors.This class of enzymes is of particular interest and concern owing to theability of many of them to hydrolyze and, thus, provide resistance to virtuallyall classes of beta-lactams.In a previous work, we identified a reactionintermediate during the hydrolysis of imipenem by BcII MBL and our unpublishedresults indicate that this intermediate is common to all three MBL subclasses.Here we present a biochemical and structural characterization of four novelbisthiazolidine compounds that mimic the structure of the intermediate and actas broad spectrum MBL inhibitors. These findings highlight the importance ofexploiting mechanistic information in order to develop enzyme inhibitors.