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Structural studies suggest aggregation as one of the modes of action for teixobactin.
Chemical Science ( IF 7.6 ) Pub Date : 2018-09-20 , DOI: 10.1039/c8sc03655a
Carl Öster 1 , Grzegorz P Walkowiak 1, 2 , Dallas E Hughes 3 , Amy L Spoering 3 , Aaron J Peoples 3 , Anita C Catherwood 2 , Julie A Tod 2 , Adrian J Lloyd 2 , Torsten Herrmann 4 , Kim Lewis 5 , Christopher G Dowson 2 , Józef R Lewandowski 1
Affiliation  

Teixobactin is a new promising antibiotic that targets cell wall biosynthesis by binding to lipid II and has no detectable resistance thanks to its unique but yet not fully understood mechanism of operation. To aid in the structure-based design of teixobactin analogues with improved pharmacological properties, we present a 3D structure of native teixobactin in membrane mimetics and characterise its binding to lipid II through a combination of solution NMR and fast (90 kHz) magic angle spinning solid state NMR. In NMR titrations, we observe a pattern strongly suggesting interactions between the backbone of the C-terminal "cage" and the pyrophosphate moiety in lipid II. We find that the N-terminal part of teixobactin does not only act as a membrane anchor, as previously thought, but is actively involved in binding. Moreover, teixobactin forms a well-structured and specific complex with lipid II, where the N-terminal part of teixobactin assumes a β conformation that is highly prone to aggregation, which likely contributes to the antibiotic's high bactericidal efficiency. Overall, our study provides several new clues to teixobactin's modes of action.

中文翻译:


结构研究表明聚集是替肖巴汀的作用方式之一。



Teixobactin 是一种新型有前途的抗生素,通过与脂质 II 结合来靶向细胞壁生物合成,并且由于其独特但尚未完全了解的作用机制,没有可检测到的耐药性。为了帮助基于结构设计具有改进药理特性的 teixobactin 类似物,我们展示了膜模拟物中天然 teixobactin 的 3D 结构,并通过溶液 NMR 和快速 (90 kHz) 魔角旋转固体的组合表征其与脂质 II 的结合状态核磁共振。在 NMR 滴定中,我们观察到一种模式,强烈表明 C 端“笼”的主链与脂质 II 中的焦磷酸部分之间存在相互作用。我们发现 teixobactin 的 N 端部分不仅像以前认为的那样充当膜锚,而且还积极参与结合。此外,teixobactin 与脂质 II 形成结构良好的特异性复合物,其中 teixobactin 的 N 末端部分呈现极易聚集的 β 构象,这可能有助于抗生素的高杀菌效率。总体而言,我们的研究为 teixobactin 的作用模式提供了一些新线索。
更新日期:2018-09-20
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