CONICET | Buscador de Institutos y Recursos Humanos

The b-lactam antibiotic family represents the largest group of commercial antibiotics clinically used to treat Gram-negative and Gram-positive infections.1 The synthesis of b-lactamases is the most widely spread resistance mechanisms displayed by bacteria. b-Lactamases are hydrolytic enzymes that selectively cleave the four-membered b-lactam ring, rendering antibiotics ineffective against their natural targets. There are four molecular classes of b-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-b-Lactamases (MBLs) are divided into three subclasses, B1, B2, and B3, all exhibiting resistance to commercially available b-lactamase inhibitors.2 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 b-lactams. In a previous work, we identified a reaction intermediate during the hydrolysis of imipenem by BcII MBL3 and our unpublished results indicate that this intermediate is common to all three MBL subclasses.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. References: 1. Fisher, J. F., Meroueh, S. O., and Mobashery, S. Chem. Rev. 105, 395-424, 2005 2. Crowder, M. W., Spencer, J., and Vila, A. J. Acc. Chem. Res. 39, 721-728, 2006 3. Tioni, M. F. et al. J. Am. Chem. Soc. 130, 15852-15863, 2008 Acknowledgements: ANPCyT, NIH, CONICET