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

Artikel i vetenskaplig tidskrift
Författare Y. Xiang
Y. J. Zhang
Y. Ge
Y. J. Zhou
C. Chen
Weixiao Yuan Wahlgren
X. S. Tan
X. Chen
K. W. Yang
Publicerad i Biomolecules
Volym 10
Nummer/häfte 1
Sidor 12
ISSN 2218-273X
Publiceringsår 2020
Publicerad vid Institutionen för kemi och molekylärbiologi
Sidor 12
Språk en
Länkar dx.doi.org/10.3390/biom10010072
Ämnesord antibiotic resistance, metallo-beta-lactamase VIM-2 inhibitor, 2-triazolylthioacetamides, thermodynamics, crystallographic study, pseudomonas-aeruginosa, scaffold, triazolylthioacetamide, azolylthioacetamides, resistance, discovery, leads, Biochemistry & Molecular Biology
Ämneskategorier Biokemi och molekylärbiologi

Sammanfattning

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.

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