Elucidation of the Teixobactin Pharmacophore.
Elucidation of the Teixobactin Pharmacophore.
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DOI：
10.1021/acschembio.6b00295
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发表时间：
2016-07-15
影响因子：
4
通讯作者：
Nowick JS
中科院分区：
文献类型：
--
作者：
Yang H;Chen KH;Nowick JS
本文通过比较teixobactin Arg10-teixobactin的精氨酸类似物与七种不同结构和立体化学的同系物来阐明teixobactin的药效团。研究了位置10的胍基、大内酯环的立体化学以及由残基1-5组成的“尾”的作用。在最低抑菌浓度(MIC)试验中，10-替克生丁基团对革兰氏阳性菌的活性高于Arg10-替克生丁基。大内酯环的相对立体化学很重要，非对映异构体L-Thr8、Arg10-teixobactin活性较低，非对映异构体d-allo-Ile11、Arg10-teixobactin活性较低。大内酯环是关键的；Seco-Arg10-teixobactin是不活跃的。绝对的立体化学并不重要；对映体-Arg10-teixobactin的活性与之相当。疏水的N-末端尾巴很重要；残基1-5的截短会导致活性的丧失，而残基1-5被十二烷酰基取代部分恢复活性。这些发现为开发更简单的teixobactin同系物铺平了道路，具有增强的药理作用。
This paper elucidates the teixobactin pharmacophore by comparing the arginine analogue of teixobactin Arg10-teixobactin to seven homologues with varying structure and stereochemistry. The roles of the guanidinium group at position 10, the stereochemistry of the macrolactone ring, and the “tail” comprising residues 1–5 are investigated. The guanidinium group is not necessary for activity; Lys10-teixobactin is more active than Arg10-teixobactin against gram-positive bacteria in minimum inhibitory concentration (MIC) assays. The relative stereochemistry of the macrolactone ring is important; diastereomer l-Thr8,Arg10-teixobactin is inactive, and diastereomer d-allo-Ile11,Arg10-teixobactin is less active. The macrolactone ring is critical; seco-Arg10-teixobactin is inactive. The absolute stereochemistry is not important; the enantiomer ent-Arg10-teixobactin is comparable in activity. The hydrophobic N-terminal tail is important; truncation of residues 1–5 results in loss of activity, and replacement of residues 1–5 with a dodecanoyl group partially restores activity. These findings pave the way for developing simpler homologues of teixobactin with enhanced pharmacological properties.