The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics
The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics
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DOI：
10.1038/nsmb830
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发表时间：
2004-10-01
影响因子：
16.8
通讯作者：
van Nuland, NAJ
中科院分区：
文献类型：
--
作者：
Hsu, STD;Breukink, E;van Nuland, NAJ
新出现的抗生素耐药性问题凸显了对新型抗菌药物的迫切需求。羊毛硫抗生素（含有羊毛硫氨酸的抗生素）是缓解这一问题的有希望的候选者。乳链菌肽是该家族的一员，具有独特的抗细菌造孔活性。它与脂质 II 结合，脂质 II 是细胞壁合成的重要前体。结果，乳链菌肽的膜透化活性增加了三个数量级。在这里，我们报告了乳链菌肽和脂质 II 复合物的溶液结构。该结构显示了一种新的脂质 II 结合基序，其中脂质 II 的焦磷酸部分主要通过分子间氢键与乳链菌肽的 N 末端骨架酰胺配位。这种笼状结构为几种脂质 II 结合羊毛硫抗生素中羊毛硫氨酸环的保守提供了理论依据。焦磷酸笼的结构为新型抗生素的基于结构的设计提供了模板。
The emerging antibiotics-resistance problem has underlined the urgent need for novel antimicrobial agents. Lantibiotics (lanthionine-containing antibiotics) are promising candidates to alleviate this problem. Nisin, a member of this family, has a unique pore-forming activity against bacteria. It binds to lipid II, the essential precursor of cell wall synthesis. As a result, the membrane permeabilization activity of nisin is increased by three orders of magnitude. Here we report the solution structure of the complex of nisin and lipid II. The structure shows a novel lipid II binding motif in which the pyrophosphate moiety of lipid II is primarily coordinated by the N-terminal backbone amides of nisin via intermolecular hydrogen bonds. This cage structure provides a rationale for the conservation of the lanthionine rings among several lipid II-binding lantibiotics. The structure of the pyrophosphate cage offers a template for structure-based design of novel antibiotics.