PUBLICATION
((S)-3-Mercapto-2-methylpropanamido)acetic acid derivatives as metallo-β-lactamase inhibitors: Synthesis, kinetic and crystallographic studies
- Authors
- Liu, S., Jing, L., Yu, Z.J., Wu, C., Zheng, Y., Zhang, E., Chen, Q., Yu, Y., Guo, L., Wu, Y., Li, G.B.
- ID
- ZDB-PUB-180123-1
- Date
- 2018
- Source
- European Journal of Medicinal Chemistry 145: 649-660 (Journal)
- Registered Authors
- Keywords
- Antibacterial resistance, Crystallography, Inhibitor design, Metallo-β-lactamase (MBL), VIM-2
- MeSH Terms
-
- Acetates/chemical synthesis
- Acetates/chemistry
- Acetates/pharmacology*
- Animals
- Cell Survival/drug effects
- Crystallography, X-Ray
- Dose-Response Relationship, Drug
- HEK293 Cells
- Humans
- Kinetics
- Models, Molecular
- Molecular Structure
- Structure-Activity Relationship
- Zebrafish
- beta-Lactamase Inhibitors/chemical synthesis
- beta-Lactamase Inhibitors/chemistry
- beta-Lactamase Inhibitors/pharmacology*
- beta-Lactamases/metabolism*
- PubMed
- 29353720 Full text @ Eur. J. Med. Chem.
Citation
Liu, S., Jing, L., Yu, Z.J., Wu, C., Zheng, Y., Zhang, E., Chen, Q., Yu, Y., Guo, L., Wu, Y., Li, G.B. (2018) ((S)-3-Mercapto-2-methylpropanamido)acetic acid derivatives as metallo-β-lactamase inhibitors: Synthesis, kinetic and crystallographic studies. European Journal of Medicinal Chemistry. 145:649-660.
Abstract
The emergence and global spread of metallo-β-lactamase (MBL) mediated resistance to almost all β-lactam antibacterials poses a serious threat to public health. Since no clinically useful MBL inhibitors have been reported, there is an urgent need to develop new potent broad-spectrum MBL inhibitors effective against antibacterial resistance. Herein, we synthesized a set of 2-substituted ((S)-3-mercapto-2-methylpropanamido) acetic acid derivatives, some of which displayed potent inhibition with high ligand efficiency to the clinically relevant MBL subtypes, Verona Integron-encoded MBL (VIM)-2 and New Delhi MBL (NDM)-1. Kinetic studies revealed that the inhibitors are not strong zinc chelators in solution, and they bind reversibly to VIM-2 but dissociate very slowly. Crystallographic analyses revealed that they inhibit VIM-2 via chelating the active site zinc ions and interacting with catalytically important residues. Further cell- and zebrafish-based assays revealed that the inhibitors slightly increase susceptibility of E. coli cells expressing VIM-2 to meropenem, and they have no apparent toxicity to the viability of HEK293T cells and the zebrafish embryogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping