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The structure of the metallo‐β‐lactamase VIM‐2 in complex with a triazolylthioacetamide inhibitor
Author(s) -
Christopeit Tony,
Yang Ke-Wu,
Yang Shao-Kang,
Leiros Hanna-Kirsti S.
Publication year - 2016
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 37
ISSN - 2053-230X
DOI - 10.1107/s2053230x16016113
Subject(s) - active site , binding site , antibiotics , chemistry , enzyme , microbiology and biotechnology , stereochemistry , biochemistry , biology
The increasing number of pathogens expressing metallo‐β‐lactamases (MBLs), and in this way achieving resistance to β‐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 β‐lactam antibiotics. However, an MBL inhibitor suitable for clinical use has not yet been identified. Verona integron‐encoded metallo‐β‐lactamase 2 (VIM‐2) is a widespread MBL with a broad substrate spectrum and hence is an interesting drug target for the treatment of β‐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 IC 50 of 20 µ M . 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 Å. 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.