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The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases
Open AccessArticle

Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-β-Lactamase 2 (VIM-2) Inhibitor

1
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Laboratory, College of Chemistry and Materials Science, Northwest University, Xi’an 710127, China
2
School of Physical Education, Yan’an University, Yan’an 716000, China
3
Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China
4
Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, S-40530 Gothenburg, Sweden
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(1), 72; https://doi.org/10.3390/biom10010072
Received: 3 December 2019 / Revised: 19 December 2019 / Accepted: 24 December 2019 / Published: 1 January 2020
(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)
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 1aj inhibited VIM-2, exhibiting an IC50 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. 1aj (16 mg/mL) restored the antibacterial activity of cefazolin against E. coli 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 (1b, 1c, or 1h) to VIM-2 was a combination of entropy and enthalpy contributions. Further, the crystal structure of VIM-2 in complex with 1b was obtained by co-crystallization with a hanging-drop vapour-diffusion method. The crystal structure analysis revealed that 1b 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. View Full-Text
Keywords: antibiotic resistance; metallo-β-lactamase VIM-2 inhibitor; 2-triazolylthioacetamides; thermodynamics; crystallographic study antibiotic resistance; metallo-β-lactamase VIM-2 inhibitor; 2-triazolylthioacetamides; thermodynamics; crystallographic study
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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-β-Lactamase 2 (VIM-2) Inhibitor. Biomolecules 2020, 10, 72.

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