Citation: Youzhen Ma, Yongxi Liang, Menglu Guo, Delin Min, Lulu Zheng, Yun Tang, Xun Sun. Strategic design of lysine-targeted irreversible covalent NDM-1 inhibitors[J]. Chinese Chemical Letters, ;2023, 34(7): 108072. doi: 10.1016/j.cclet.2022.108072 shu

Strategic design of lysine-targeted irreversible covalent NDM-1 inhibitors

Youzhen Ma ^a ,
Yongxi Liang ^a ,
Menglu Guo ^a ,
Delin Min ^a ,
Lulu Zheng ^c ,
Yun Tang ^c ,
Xun Sun ^{a, b, *,}

a.
Department of Natural Medicine, School of Pharmacy, Fudan University, Shanghai 201203, China
b.
The Institutes of Integrative Medicine of Fudan University, Shanghai 200040, China
c.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

sunxunf@shmu.edu.c

Received Date: 30 August 2022
Revised Date: 24 November 2022
Accepted Date: 12 December 2022
Available Online: 14 December 2022

Figures(6)

New Delhi metallo-β-lactamase 1 (NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relatively weak due to the shallow active pocket of NDM-1. Alternatively, irreversible covalent inhibitors can prevent their dissociation from the target, leading to permanent inactivation of the protein. Herein, we report a series of irreversible covalent inhibitors of NDM-1 targeting the conserved Lys211 in the active pocket. Several methods, including mass spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fluorescent labeling, and coumarin probe were used to demonstrate that pentafluorophenyl ester formed a covalent bond with Lys211. Moreover, our target inhibitor, in combination with meropenem, achieved an antibacterial effect on drug-resistant bacteria, along with an excellent safety profile. Our new strategy in designing lysine-targeted irreversible covalent NDM-1 inhibitors provides a potential option for the clinical treatment of Gram-negative bacteria.
- Covalent inhibitors,
- Lysine,
- Irreversible,
- Metallo-β-lactamase,
- Antimicrobial activity
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