Disulfiram as a potent metallo-β-lactamase inhibitor with dual functional mechanisms

• Published in: Chemical communications (Cambridge, England) Vol. 56; no. 18; pp. 2755 - 2758
• Main Authors: Chen, Cheng, Yang, Ke-Wu, Wu, Lin-Yu, Li, Jia-Qi, Sun, Le-Yun
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 04.03.2020
• Subjects: beta-lactamase; beta-Lactamase Inhibitors - chemistry; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases - metabolism; chemical bonding; chemical reactions; Copper; disulfiram; Disulfiram - chemistry; Disulfiram - pharmacology; enzyme inhibitors; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - metabolism; Inhibitors; Metabolites; Metallography; Models, Molecular; Molecular Structure; Oxidation; zinc
• ISSN: 1359-7345; 1364-548X; 1364-548X
• DOI: 10.1039/c9cc09074f

We report a promising NDM-1 inhibitor, disulfiram, which can covalently bind to NDM-1 by forming an S-S bond with the Cys208 residue. Its copper-containing metabolite in vivo , Cu(DTC) 2 , also inactivated NDM-1 through oxidizing the Zn( ii ) thiolate site of the enzyme, therefore exhibiting dual functional inhibitory potential against B1 and B2 subclass MβLs. We report a promising NDM-1 inhibitor, disulfiram, which can covalently bind to NDM-1 by forming an S-S bond with the Cys208 residue. Cu(DTC) 2 also inactivated NDM-1 through oxidizing the Zn( ii ) thiolate site of the enzyme.