5LSC

The structure of the metallo-beta-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor

Summary for 5LSC

• Entry DOI: 10.2210/pdb5lsc/pdb
• Descriptor: Metallo-beta-lactamase VIM-2-like protein, CHLORIDE ION, 2-[5-[2-(1,3-benzothiazol-2-ylamino)-2-oxidanylidene-ethyl]sulfanyl-4~{H}-1,2,4-triazol-3-yl]benzoic acid, ... (5 entities in total)
• Functional Keywords: antibiotic resistance, carbapenemases, verona integron-encoded metallo-beta-lactamase 2, vim-2, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 52506.73

Authors

Christopeit, T.,Yang, K.-W.,Yang, S.-K.,Leiros, H.-K.S. (deposition date: 2016-08-25, release date: 2016-11-09, Last modification date: 2024-01-17)

Primary citation

Christopeit, T.,Yang, K.W.,Yang, S.K.,Leiros, H.K.
The structure of the metallo-beta-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor.
Acta Crystallogr F Struct Biol Commun, 72:813-819, 2016

PubMed Abstract: 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 of 20 µM. 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.

PubMed: 27834790
DOI: 10.1107/S2053230X16016113

Experimental method

X-RAY DIFFRACTION (1.497 Å)