| Summary: | 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 <b>1a</b>−<b>j</b> inhibited VIM-2, exhibiting an IC<sub>50</sub> 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. <b>1a</b>−<b>j</b> (16 mg/mL) restored the antibacterial activity of cefazolin against <i>E. coli</i> 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 (<b>1b</b>, <b>1c</b>, or <b>1h</b>) to VIM-2 was a combination of entropy and enthalpy contributions. Further, the crystal structure of VIM-2 in complex with <b>1b</b> was obtained by co-crystallization with a hanging-drop vapour-diffusion method. The crystal structure analysis revealed that <b>1b</b> 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.
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