Abstract

Background: The appearance of antibiotic resistance caused by metallo-β-lactamases (MβLs) is a global public health threat. Developing MβLs inhibitor is an effective way to overcome antibiotic resistance. Recently, azolylthioacetamides were reported to be promising MβLs inhibitors.

Methods: Triazolylthioacetamides were synthesized and tested for inhibition activity against the purified MβL IMP-1. Antimicrobial activities of these inhibitors in combination with cefazolin were evaluated. Isothermal Titration Calorimetry (ITC) was employed to characterize the binding of the inhibitor to IMP-1, and their action mechanism was studied by molecular docking.

Results: Twenty compounds exhibited specific inhibitory activity against IMP-1 with an IC50 value in the range of 3.1-62.5 μM. Eight of the compounds can restore the antibacterial efficacy of cefazolin against E. coli BL21 strain producing IMP-1 by 2-4 fold. ITC monitoring showed that 1c exhibited dose-dependent inhibition on IMP-1. Docking studies revealed that the triazole group in 1c and 2d played an essential role in the inhibition activity. Cytotoxicity assay showed that 1c and 2d have low toxicity in L929 mouse fibroblastic cells.

Conclusion: The triazolylthioacetamides are efficient inhibitors of IMP-1 in vitro and in vivo.

Keywords: Antibiotic resistance, β-lactam, metallo-β-lactamases, IMP-1, triazolylthioacetamides, inhibitor.

Graphical Abstract