Öster Carl, Walkowiak Grzegorz P, Hughes Dallas E, Spoering Amy L, Peoples Aaron J, Catherwood Anita C, Tod Julie A, Lloyd Adrian J, Herrmann Torsten, Lewis Kim, Dowson Christopher G, Lewandowski Józef R
Department of Chemistry , University of Warwick , Coventry , CV4 7AL , UK . Email:
School of Life Sciences , University of Warwick , Coventry , CV4 7AL , UK.
Chem Sci. 2018 Sep 20;9(47):8850-8859. doi: 10.1039/c8sc03655a. eCollection 2018 Dec 21.
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.
替考拉宁是一种新的、有前景的抗生素，它通过与脂质II结合来靶向细胞壁生物合成，由于其独特但尚未完全理解的作用机制，目前尚未检测到耐药性。为了帮助设计具有改善药理特性的替考拉宁类似物的基于结构的设计，我们展示了在膜模拟物中天然替考拉宁的三维结构，并通过溶液核磁共振（NMR）和快速（90 kHz）魔角旋转固态核磁共振相结合的方法，对其与脂质II的结合进行了表征。在核磁共振滴定中，我们观察到一种强烈表明C末端“笼”的主链与脂质II中的焦磷酸部分之间存在相互作用的模式。我们发现，替考拉宁的N末端部分不仅如先前认为的那样作为膜锚定物起作用，而且还积极参与结合。此外，替考拉宁与脂质II形成了一种结构良好且特异的复合物，其中替考拉宁的N末端部分呈现出一种极易聚集的β构象，这可能有助于抗生素的高杀菌效率。总体而言，我们的研究为替考拉宁的作用模式提供了几个新线索。
