1. Recent research and development of NDM-1 inhibitors.
- Author
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Wang, Ting, Xu, Kaiju, Zhao, Liyun, Tong, Rongsheng, Xiong, Liang, and Shi, Jianyou
- Subjects
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BETA lactam antibiotics , *VESICLES (Cytology) , *ANTIBIOTICS , *DRUG resistance in bacteria , *AMINO acid residues , *ZINC ions , *ZINC porphyrins , *FLEXIBLE structures - Abstract
Bacteria carrying New Delhi metallo-β-lactamase-1 (New Delhi metallo-β-lactamase, NDM-1) resistance gene is a new type of "superbug", which can hydrolyze almost all β-lactam antibiotics, rapidly spread among the same species and even spread among different species. NDM-1 belongs to the class B1 broad-spectrum enzyme of β-lactamase. The two positively charged zinc ions in the active center have electrostatic interaction with the hydroxyl ions in them to seize the hydrogen atom near the water molecule to form a bridging ring water molecule, which strengthens its nucleophilicity and attacks the carbonyl group on the lactam ring; thus, catalyzing the hydrolysis of β-lactam antibiotics. Since NDM-1 has an open active site and unique electrostatic structure, it essentially provides a wider range of substrate specificity. Due to its flexible hydrolysis mechanism and more and more variants also aggravate the threat of drug-resistant bacteria infection, there is still no effective inhibitor in clinic, which is a serious threat to human health and public health safety. The electron-rich substituents of NDM-1 inhibitors coordinate with two positively charged zinc ions in the active center of the enzyme through ion-dipole interaction to produce NDM-1 inhibitory activity. In this review, the research progress of NDM-1 enzyme and its inhibitors in the past 5 years was reviewed. The crystal structure, active center structure, surrounding important amino acid residues, newly discovered inhibitors and their action mechanism are classified and summarized in detail, which can be used as a reference for the development of effective drugs against drug-resistant bacteria targeting NDM-1. Most of the blaNDM-1 genes are located in plasmids, which are obtained by transposition, which can be stably transmitted in drug-resistant strains and secreted out of cells through outer membrane vesicle (OMVs), giving drug resistance to nearby bacteria. And the compounds mentioned in the article in which IC50 is less than 5 μM. [Display omitted] • NDM-1 enzyme can hydrolyze almost all β-lactam antibiotics. • NDM-1 has open active sites,unique electrostatic structure and flexible hydrolysis mechanism. • NDM-1 inhibitors are divided into three categories according to its mechanism of action. • NDM-1 inhibitors can act on zinc ions and key amino acid residues. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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