5lsc

Publication Abstract from PubMed

The increasing number of pathogens expressing metallo-beta-lactamases (MBLs), and in this way achieving resistance to beta-lactam antibiotics, is a significant threat to global public health. A promising strategy to treat such resistant pathogens is the co-administration of MBL inhibitors together with beta-lactam antibiotics. However, an MBL inhibitor suitable for clinical use has not yet been identified. Verona integron-encoded metallo-beta-lactamase 2 (VIM-2) is a widespread MBL with a broad substrate spectrum and hence is an interesting drug target for the treatment of beta-lactam-resistant infections. In this study, three triazolylthioacetamides were tested as inhibitors of VIM-2. One of the tested compounds showed clear inhibition of VIM-2, with an IC50 of 20 microM. The crystal structure of the inhibitor in complex with VIM-2 was obtained by DMSO-free co-crystallization and was solved at a resolution of 1.50 A. To our knowledge, this is the first structure of a triazolylthioacetamide inhibitor in complex with an MBL. Analysis of the structure shows that the inhibitor binds to the two zinc ions in the active site of VIM-2 and revealed detailed information on the interactions involved. Furthermore, the crystal structure showed that binding of the inhibitor induced a conformational change of the conserved residue Trp87.

The structure of the metallo-beta-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor.,Christopeit T, Yang KW, Yang SK, Leiros HK Acta Crystallogr F Struct Biol Commun. 2016 Nov 1;72(Pt 11):813-819. Epub 2016, Oct 24. PMID:27834790^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.