Mechanism-based design of four novel metallo beta-lactamase broad spectrum bisthiazolidine inhibitors

GONZALEZ MARIANO; PALACIOS, ANTONELA; CASTILLO, V; J.M. GONZALEZ; LLARRULL LI; MAHLER,G; A. J. VILA

Berlín

Congreso; 23rd ECCMID; 2013

The beta-lactam antibiotic family represents the largest group of commercial antibiotics clinically used to treat Gram-negative and Gram-positive infections. The synthesis of beta-lactamases is the most widely spread resistance mechanisms displayed by bacteria. beta-Lactamases are hydrolytic enzymes that selectively cleave the four-membered beta-lactam ring, rendering antibiotics ineffective against their natural targets. There are four molecular classes of beta-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, and B3, all exhibiting resistance to commercially available beta-lactamase inhibitors. This class of enzymes is of particular interest and concern owing to the ability of many of them to hydrolyze and, thus, provide resistance to virtually all classes of beta-lactams. In a previous work, we identified a reaction intermediate during the hydrolysis of imipenem by BcII MBL and our unpublished results indicate that this intermediate is common to all three MBL subclasses. Here we present a biochemical and structural characterization of four novel bisthiazolidine compounds that mimic the structure of the intermediate and act as broad spectrum MBL inhibitors. These findings highlight the importance of exploiting mechanistic information in order to develop enzyme inhibitors.