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Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-β-Lactamase 2 (VIM-2) Inhibitor
- Source :
- Biomolecules, Vol 10, Iss 1, p 72 (2020), Biomolecules, Volume 10, Issue 1
- Publication Year :
- 2020
- Publisher :
- MDPI AG, 2020.
-
Abstract
- Inhibition of &beta<br />lactamases presents a promising strategy to restore the &beta<br />lactams antibacterial activity to resistant bacteria. In this work, we found that aromatic carboxyl substituted 2-triazolylthioacetamides 1a&ndash<br />j inhibited VIM-2, exhibiting an IC50 value in the range of 20.6&ndash<br />58.6 &mu<br />M. 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. 1a&ndash<br />j (16 mg/mL) restored the antibacterial activity of cefazolin against E. coli cell expressing VIM-2, resulting in a 4&ndash<br />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<br />especially for the phenyl of aromatic carboxyl which formed &pi<br />&pi<br />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 M&beta<br />Ls inhibitors.
- Subjects :
- Models, Molecular
antibiotic resistance
Stereochemistry
Carboxylic acid
Stacking
lcsh:QR1-502
Crystal structure
Microbial Sensitivity Tests
Thioacetamide
Crystallography, X-Ray
01 natural sciences
Biochemistry
beta-Lactamases
Article
lcsh:Microbiology
Integrons
03 medical and health sciences
Structure-Activity Relationship
thermodynamics
Bacterial Proteins
Catalytic Domain
Escherichia coli
Molecule
Molecular Biology
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Binding Sites
crystallographic study
biology
Bacteria
Molecular Structure
010405 organic chemistry
Chemistry
2-triazolylthioacetamides
Isothermal titration calorimetry
biochemical phenomena, metabolism, and nutrition
Triazoles
metallo-β-lactamase vim-2 inhibitor
Enzyme assay
0104 chemical sciences
Anti-Bacterial Agents
Kinetics
Enzyme
biology.protein
Antibacterial activity
Protein Binding
Subjects
Details
- Language :
- English
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Biomolecules
- Accession number :
- edsair.doi.dedup.....f1638106671f3b7d752921454ea0a454