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

The Journal of Antibiotics volume 74, pages 574–579 (2021)Cite this article

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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.

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Acknowledgements

This research was funded by the Grants (22077100 and 2019KW-068 to K.W.Y) from the National Natural Science Foundation of China and Shaanxi Province International Cooperation Project and grant (17JS007 to L.Z.) from the Shaanxi Education Commission, China.

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  1. These authors contributed equally: Ying Ge, Peng-Wei Kang

Authors and Affiliations

  1. 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, P. R. China

    Ying Ge, Peng-Wei Kang, Jia-Qi Li, Han Gao, Le-Yun Sun, Cheng Chen & Ke-Wu Yang

  2. Medical College, Xijing University, Xian, China

    Ying Ge

  3. Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, Shaanxi Province, P. R. China

    Le Zhai

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Ge, Y., Kang, PW., Li, JQ. et al. Thiosemicarbazones exhibit inhibitory efficacy against New Delhi metallo-β-lactamase-1 (NDM-1). J Antibiot 74, 574–579 (2021). https://doi.org/10.1038/s41429-021-00440-3

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