新型抗生素葡糖脱乙酰基酶LpxC抑制剂研究进展  

Research advances on the inhibitors of UDP-3-O-(R-3-hydroxyacyl)-nacetylglucosamine deacetylase(LpxC) against Gram-negative bacteria

作　　者：王明华[1] 张国宁[1] 王菊仙[1] 王玉成[1] Wang Ming-hua;Zhang Guo-ning;Wang Ju-xian;Wang Yu-cheng(Institute of Medical Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所

出　　处：《中国抗生素杂志》2019年第8期887-898,共12页Chinese Journal of Antibiotics

基　　金：国家自然科学基金(No.81703366和No.81473099)

摘　　要：革兰阴性菌耐药性已经严重威胁人类健康,亟需开发新作用机制的抗菌药物。UDP-3-O-(R-羟基十四酰)-N-乙酰氨基葡糖脱乙酰基酶(LpxC)是催化合成革兰阴性菌外膜脂多糖主要成分类脂A的关键酶,在革兰阴性菌中具有较高的同源性,与哺乳动物(包括人)的各种酶都没有共同序列。LpxC的缺失或过表达都会使某些革兰阴性致病菌死亡,这使其成为具有开发前景的抗革兰阴性菌药物的全新靶标。为此,本文综述了LpxC的结构、酶学性质、催化机理及其抑制剂等研究进展。Infections caused by multidrug-resistant (MDR) Gram-negative organisms are a major health concern throughout the world, associated with high morbidity and mortality. The first irreversible step of lipid A biosynthesis was catalyzed by the UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), which is a Zn2+- dependent enzyme. The enzyme is required for growth and viability of Gram-negative bacteria, displays no sequence homology with any mammalian protein, but is highly conserved in Gram-negative bacteria. Either enhanced levels or lack of LpxC expression is lethal to some Gram-negative bacteria. Therefore, it may become a promising target in the development of novel antibiotics against Gram-negative bacteria. Thus, research on LpxC inhibitors as new antibacterial agents has become an attractive field in the development of the novel antibiotic therapy of Gram-negative bacteria. In this review, we will summarize the recent progress in the structure, enzymology, catalytic mechanism, and the research and development of LpxC inhibitors.

关 键 词：UDP-3-O-(R-3-羟基肉豆蔻酰基)-N-乙酰葡萄糖胺脱乙酰基酶(LpxC) 类脂A生物合成 LpxC酶抑制剂 革兰阴性菌 细菌感染 

分 类 号：R978[医药卫生—药品]