新型抗生素葡糖脱乙酰基酶LpxC抑制剂研究进展.pdf

中国抗生素杂志年月第卷第期 . 887 . 文章编号：-()-- 综述 新型抗生素葡糖脱乙酰基酶LpxC 抑制剂研究进展 王明华 张国宁 王菊仙 王玉成* ( 中国医学科学院北京协和医学院医药生物技术研究所，北京) 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--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。 关键词：UDP--O-(R-- 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 中图分类号：R 文献标志码：A Research advances on the inhibitors of UDP-3-O-(R-3-hydroxyacyl)- nacetylglucosamine deacetylase (LpxC) against Gram-negative bacteria Wang Ming-hua, Zhang Guo-ning, Wang Ju-xian and Wang Yu-cheng ( Institute of Medical Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050) Abstract 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