Structural and Mechanistic Insights into NDM-1 Catalyzed Hydrolysis of Cephalosporins

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• 作者：Han Feng ; Jingjin Ding ; Deyu Zhu ; Xuehui Liu ; Xueyong Xu ; Ying Zhang ; Shanshan Zang ; Da-Cheng Wang ; Wei Liu
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：October 22, 2014
• 年：2014
• 卷：136
• 期：42
• 页码：14694-14697
• 全文大小：316K
• ISSN：1520-5126

文摘

Cephalosporins constitute a large class of 尾-lactam antibiotics clinically used as antimicrobial drugs. New Dehli metallo-尾-lactamase (NDM-1) poses a global threat to human health as it confers on bacterial pathogen resistance to almost all 尾-lactams, including penicillins, cephalosporins, and carbapenems. Here we report the first crystal structures of NDM-1 in complex with cefuroxime and cephalexin, as well as NMR spectra monitoring cefuroxime and cefixime hydrolysis catalyzed by NDM-1. Surprisingly, cephalosporoate intermediates were captured in both crystal structures determined at 1.3 and 2.0 脜. These results provide detailed information concerning the mechanism and pathways of cephalosporin hydrolysis. We also present the crystal structure and enzyme assays of a D124N mutant, which reveals that D124 most likely plays a more structural than catalytic role.