2. Academic Validation
  3. Discovery of isatin-β-methyldithiocarbazate derivatives as New Delhi metallo- β-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates

Discovery of isatin-β-methyldithiocarbazate derivatives as New Delhi metallo- β-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates

  • Biomed Pharmacother. 2023 Oct:166:115439. doi: 10.1016/j.biopha.2023.115439.
Hongfa Lv 1,  Zihao Zhu 2,  Chenliang Qian 3,  Tianlei Li 2,  Zunsheng Han 2,  Wenxuan Zhang 2,  Xinxin Si 4,  Jianfeng Wang 1,  Xuming Deng 1,  Li Li 1,  Tianqi Fang 1,  Jie Xia 5,  Song Wu 6,  Yonglin Zhou 7
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
  • 4 School of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: jie.william.xia@hotmail.com.
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: ws@imm.ac.cn.
  • 7 Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, School of Life Sciences, Ningxia University, Yinchuan, China; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China. Electronic address: Zhouyonglin333@126.com.
PMID: 37673020 DOI: 10.1016/j.biopha.2023.115439
Abstract

New Delhi metallo-β-lactamase-1 (NDM-1) poses a threat to public health due to its capability to hydrolyze nearly all β-lactam Antibiotics, leaving limited treatment options for NDM-1 positive pathogens. Regrettably, there are presently no effective NDM-1 inhibitors in clinical use. This compels us to seek new compounds to combat multi-drug resistant Bacterial infections (MDR). In our study, Zndm19 was identified as a new NDM-1 inhibitor through virtual screening and an NDM-1 Enzyme activity inhibition assay. Subsequently, we employed the checkerboard method, time-killing assay, and combined disk test to investigate the synergistic bactericidal efficacy of Zndm19 in combination with meropenem (MEM). Meanwhile, molecular docking and site-directed mutagenesis were conducted to uncover the crucial amino acid residues engaged in Zndm19 binding. Finally, we established a mice peritonitis Infection model to assess the synergistic effect of Zndm19 and MEM in vivo. Our findings demonstrated that 16 µg/mL of Zndm19 inhibited NDM-1 activity without affecting NDM-1 expression, restoring the bactericidal activity of MEM against NDM-1-positive Escherichia coli in vitro. Furthermore, MET-67, ASP-124, HIS-189, and HIS-250 amino acid residues constituted the active site of Zndm19 in NDM-1. Importantly, this combination therapy exhibited synergistic Anti-infection activity in the mice peritonitis Infection model, leading to an approximate 60% increase in survival rates and reduction of tissue Bacterial load, effectively combating Bacterial infection in vivo. In summary, our research validates that the synthetic novel NDM-1 inhibitor Zndm19 holds promise as a drug to treat drug-resistant Bacterial infections, especially those harboring NDM-1.

Keywords

Machine learning; Metallo-β-lactamase inhibitors; Molecular docking; NDM-1.

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