Thiosemicarbazones exhibit inhibitory efficacy against New Delhi metallo-β-lactamase-1 (NDM-1)

Abstract

The superbug infection caused by metallo-β-lactamases (MβLs) carrying drug-resistant bacteria, specifically, New Delhi metallo-β-lactamase (NDM-1) has become an emerging threat. In an effort to develop novel inhibitors of NDM-1, thirteen thiosemicarbazones (1a-1m) were synthesized and assayed. The obtained molecules specifically inhibited NDM-1, with an IC₅₀ in the range of 0.88-20.2 µM, and 1a and 1f were found to be the potent inhibitors (IC₅₀ = 1.79 and 0.88 μM) using cefazolin as substrate. ITC and kinetic assays indicated that 1a irreversibly and non-competitively inhibited NDM-1 in vitro. Importantly, MIC assays revealed that these molecules by themselves can sterilize NDM-producing clinical isolates EC01 and EC08, exhibited 78-312-fold stronger activities than the cefazolin. MIC assays suggest that 1a (16 μg ml^-1) has synergistic antimicrobial effect with ampicillin, cefazolin and meropenem on E. coli producing NDM-1, resulting in MICs of 4-32-, 4-32-, and 4-8-fold decrease, respectively. These studies indicate that the thiosemicarbazide is a valuable scaffold for the development of inhibitors of NDM-1 and NDM-1 carrying drug-resistant bacteria.