PDF(Sci-hub)
Abstract：
Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building block L-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, with 20 and 26 identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus respectively in comparison with teixobactin. In addition, they show high efficiency in Streptococcus pneumoniae septicemia mouse model and neutropenic mouse thigh infection model using methicillin-resistant Staphylococcus 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.
摘要：
Teixobactin代表了一类新的抗生素，具有新颖的结构和对革兰氏阳性病原体和结核分枝杆菌的优异活性。在这里，我们报告了一锅反应，可在短短一小时内以30克的规模方便地构建关键的构建块L-allo-Enduracidine，并采用收敛策略（326）完成克规模的全合成teixobactin。描述了几种类似物，与Teixobactin相比，20和26被确定为最有效的类似物，其对耐万古霉素的粪肠球菌和耐甲氧西林的金黄色葡萄球菌的效力分别高3〜8倍和2〜4倍。此外,它们在肺炎链球菌败血症小鼠模型和使用耐甲氧西林金黄色葡萄球菌的中性粒细胞减少小鼠大腿感染模型中显示出很高的效率。我们还提出，teixobactin的反平行β-折叠对其生物活性很重要，teixobactin的反平行二聚体是通过关键氨基酸变异和分子对接的脂质II的最小结合单位。
