A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid a biosynthesis with antibiotic activity comparable to ciprofloxacin
A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid a biosynthesis with antibiotic activity comparable to ciprofloxacin
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DOI：
10.1021/bi0518186
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发表时间：
2005-12-20
期刊：
影响因子：
2.9
通讯作者：
Raetz, CRH
中科院分区：
文献类型：
--
作者：
McClerren, AL;Endsley, S;Raetz, CRH
依赖锌的酶LpxC催化UDP-3-O-酰基-GlcNAc的脱乙酰化，这是脂质A生物合成的第一步。类脂A是大多数革兰氏阴性细菌外膜的重要成分，包括大肠杆菌、肠沙门氏菌和铜绿假单胞菌，这使得LpxC成为抗生素设计的一个有吸引力的目标。本文报道了最近一项专利申请(授予CHIRON和华盛顿大学的国际专利WO2004/062601 A2)中的一种新型N-芳酰基-L-苏氨酸异羟肟酸(CHIR-090)对LpxC的抑制作用。CHIR-090对大肠杆菌和铜绿假单胞菌均具有显著的抗菌活性，与环丙沙星相当。CHIR-090的生物活性是因为它在低纳摩尔浓度下对包括Aquifex aeolicus在内的各种LpxC同系物的抑制作用，这些同系物的结构信息是可用的。CHIR-090对Apeolicus LpxC的抑制作用分两步进行。第一步是快速和可逆的，根据检测方法的不同，K-I为1.0-1.7纳米。第二步涉及将半衰期约为一分钟的EL络合物转换为紧密结合的形式。第二步在功能上是不可逆的，但不会导致电喷雾电离质谱仪判断的酶的共价修饰。CHIR-090是第一个针对LpxC的缓慢、紧密结合的抑制剂的例子，并可能成为具有治疗适用性的新一代LpxC抑制剂的原型。
The zinc-dependent enzyme LpxC catalyzes the deacetylation of UDP-3-O-acyl-GlcNAc, the first committed step of lipid A biosynthesis. Lipid A is an essential component of the outer membranes of most Gram-negative bacteria, including Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa, making LpxC an attractive target for antibiotic design. The inhibition of LpxC by a novel N-aroyl-L-threonine hydroxamic acid (CHIR-090) from a recent patent application (International Patent WO 2004/062601 A2 to Chiron and the University of Washington) is reported here. CHIR-090 possesses remarkable antibiotic activity against both E. coli and P. aeruginosa, comparable to that of ciprofloxacin. The biological activity of CHIR-090 is explained by its inhibition of diverse LpxC orthologues at low nanomolar concentrations, including that of Aquifex aeolicus, for which structural information is available. The inhibition of A. aeolicus LpxC by CHIR-090 occurs in two steps. The first step is rapid and reversible, with a K-i of 1.0-1.7 nM, depending upon the method of assay. The second step involves the conversion of the El complex with a half-life of about a minute to a tightly bound form. The second step is functionally irreversible but does not result in the covalent modification of the enzyme, as judged by electrospray ionization mass spectrometry. CHIR-090 is the first example of a slow, tight-binding inhibitor for LpxC and may be the prototype for a new generation of LpxC inhibitors with therapeutic applicability.