Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
复制标题
克级全合成teixobactin促进结合模式研究和更有效抗生素的发现
DOI：
10.1038/s41467-019-11211-y
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发表时间：
2019-07-22
影响因子：
16.6
通讯作者：
Rao, Yu
中科院分区：
文献类型：
--
作者：
Zong, Yu;Fang, Fang;Rao, Yu
泰克菌素是一类结构新颖、对革兰氏阳性菌和结核分枝杆菌具有良好抗菌活性的新型抗生素。在此，我们报道了一锅反应，以方便地构建30克规模的关键构件1-allo-Enduracidine，仅需1小时，以及收敛策略（3 + 2 + 6），以实现克规模的teixobactin的全合成。其中20和26是最有效的类似物，对耐万古霉素粪肠球菌和耐甲氧西林金黄色葡萄球菌的活性分别是替沙菌素的3~8倍和2~4倍。此外，它们在使用耐甲氧西林金黄色葡萄球菌的肺炎链球菌败血症小鼠模型和肺炎链球菌败血症小鼠大腿感染模型中显示出高效率。我们还提出，teixobactin的反平行β-折叠对于其生物活性是重要的，并且teixobactin的反平行二聚体是通过关键氨基酸变异和分子对接与脂质II结合的最小单元。
Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens andMycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building blockl-allo-Enduracidine in 30-gram scale in just one hour and a convergent strategy (3 + 2 + 6) to accomplish a gram-scale total synthesis of teixobactin. Several analogs are described, with20and26identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistantEnterococcus faecalisand methicillin-resistantStaphylococcus aureusrespectively in comparison with teixobactin. In addition, they show high efficiency inStreptococcus pneumoniaesepticemia mouse model and neutropenic mouse thigh infection model using methicillin-resistantStaphylococcus aureus. We also propose that the antiparallel β-sheet of teixobactin is important for its bioactivity and an antiparallel dimer of teixobactin is the minimal binding unit for lipid II via key amino acids variations and molecular docking.