6KW1

The structure of the metallo-beta-lactamase VIM-2 in complex with a triazolylthioacetamide 1b

Summary for 6KW1

• Entry DOI: 10.2210/pdb6kw1/pdb
• Descriptor: Beta-lactamase class B VIM-2, ZINC ION, CHLORIDE ION, ... (9 entities in total)
• Functional Keywords: antibiotic resistant, metallo-beta-lactamase vim-2 inhibitor, trizolylthioacetamides, crystallographic study, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 58248.64

Authors

Yang, K.W.,Xiang, Y. (deposition date: 2019-09-05, release date: 2020-09-09, Last modification date: 2023-11-22)

Primary citation

Xiang, Y.,Zhang, Y.J.,Ge, Y.,Zhou, Y.,Chen, C.,Wahlgren, W.Y.,Tan, X.,Chen, X.,Yang, K.W.
Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-beta-Lactamase 2 (VIM-2) Inhibitor.
Biomolecules, 10:-, 2020

PubMed Abstract: Inhibition of β-lactamases presents a promising strategy to restore the β-lactams antibacterial activity to resistant bacteria. In this work, we found that aromatic carboxyl substituted 2-triazolylthioacetamides - inhibited VIM-2, exhibiting an IC value in the range of 20.6-58.6 μM. The structure-activity relationship study revealed that replacing the aliphatic carboxylic acid with aromatic carboxyl improved the inhibitory activity of 2-triazolylthioacetamides against VIM-2. - (16 mg/mL) restored the antibacterial activity of cefazolin against cell expressing VIM-2, resulting in a 4-8-fold reduction in MICs. The isothermal titration calorimetry (ITC) characterization suggested that the primary binding 2-triazolylthioacetamide (, , or ) to VIM-2 was a combination of entropy and enthalpy contributions. Further, the crystal structure of VIM-2 in complex with was obtained by co-crystallization with a hanging-drop vapour-diffusion method. The crystal structure analysis revealed that bound to two Zn(II) ions of the enzyme active sites, formed H-bound with Asn233 and structure water molecule, and interacted with the hydrophobic pocket of enzyme activity center utilizing hydrophobic moieties; especially for the phenyl of aromatic carboxyl which formed π-π stacking with active residue His263. These studies confirmed that aromatic carboxyl substituted 2-triazolylthioacetamides are the potent VIM-2 inhibitors scaffold and provided help to further optimize 2-triazolylthioacetamides as VIM-2 even or broad-spectrum MβLs inhibitors.

PubMed: 31906402
DOI: 10.3390/biom10010072

Experimental method

X-RAY DIFFRACTION (1.77521201035 Å)