Discovery of Potential Antituberculosis Agents Targeted Methionine Aminopeptidase 1 of Mycobacterium tuberculosis by the Developed Fluorescent Probe

  • Anal Chem. 2023 Nov 7;95(44):16210-16215. doi: 10.1021/acs.analchem.3c02952.
Ming Zhang  1  2 ,  Shengui He  3 ,  Xiuyan Han  1 ,  Jingnan Cui  3 ,  Honglei Wang  2 ,  Xiaokui Huo  1 ,  Fei Yan  1 ,  Lei Feng  1  4 ,  Chao Wang  1  2 ,  Xiaochi Ma  1  5
Affiliations
  • 1. Second Affiliated Hospital, Dalian Medical University, Dalian 116044, China.
  • 2. Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
  • 3. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China.
  • 4. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China.
  • 5. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
PMID: 37899593 DOI: 10.1021/acs.analchem.3c02952
Abstract

Tuberculosis (TB) is a chronic systemic infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis). Methionine Aminopeptidase 1 (MtMET-AP1) is a hydrolase that mediates the necessary post-translational N-terminal methionine excision (NME) of peptides during protein synthesis, which is necessary for Bacterial proliferation and is a potential target for the treatment of tuberculosis. Based on the functional characteristics of MtMET-AP1, we developed an enzymatic activated near-infrared fluorescent probe DDAN-MT for rapid, highly selective, and real-time monitoring of endogenous MtMET-AP1 activity in M. tuberculosis. Using the probe DDAN-MT, a visually high-throughput screening technique was established, which obtained three potential inhibitors (GSK-J4 hydrochchloride, JX06, and lavendustin C) against MtMET-AP1 from a 2560 compounds library. More importantly, these inhibitors could inhibit the growth of M. tuberculosis H37Ra especially (MICs < 5 μM), with low toxicities on intestinal bacteria strains and human cells. Therefore, the visual sensing of MtMET-AP1 was successfully performed by DDAN-MT, and MtMET-AP1 inhibitors were discovered as potential antituberculosis agents.

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