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Kinetic, Thermodyna...
Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-beta-Lactamase 2 (VIM-2) Inhibitor
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Xiang, Y. (author)
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Zhang, Y. J. (author)
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Ge, Y. (author)
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Zhou, Y. J. (author)
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Chen, C. (author)
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- Wahlgren, Weixiao Yuan, 1970 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Tan, X. S. (author)
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Chen, X. (author)
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Yang, K. W. (author)
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(creator_code:org_t)
- 2020-01-01
- 2020
- English.
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In: Biomolecules. - : MDPI AG. - 2218-273X. ; 10:1
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https://www.mdpi.com...
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https://gup.ub.gu.se...
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https://doi.org/10.3...
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Abstract
Subject headings
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- Inhibition of beta-lactamases presents a promising strategy to restore the beta-lactams antibacterial activity to resistant bacteria. In this work, we found that aromatic carboxyl substituted 2-triazolylthioacetamides 1a-j inhibited VIM-2, exhibiting an IC50 value in the range of 20.6-58.6 mu 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-j (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 pi-pi 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 Ls inhibitors.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- antibiotic resistance
- metallo-beta-lactamase VIM-2 inhibitor
- 2-triazolylthioacetamides
- thermodynamics
- crystallographic study
- pseudomonas-aeruginosa
- scaffold
- triazolylthioacetamide
- azolylthioacetamides
- resistance
- discovery
- leads
- Biochemistry & Molecular Biology
Publication and Content Type
- ref (subject category)
- art (subject category)
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