Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-β-Lactamase 2 (VIM-2) Inhibitor
Yang Xiang,
Yue-Juan Zhang,
Ying Ge,
Yajun Zhou,
Cheng Chen,
Weixiao Yuan Wahlgren,
Xiangshi Tan,
Xi Chen,
Ke-Wu Yang
Affiliations
Yang Xiang
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
Yue-Juan Zhang
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
Ying Ge
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
Yajun Zhou
Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China
Cheng Chen
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
Weixiao Yuan Wahlgren
Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, S-40530 Gothenburg, Sweden
Xiangshi Tan
Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China
Xi Chen
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
Ke-Wu Yang
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
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 1a−j 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. 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 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.
