MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 100084, Beijing, China.
Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, MA, 02115, USA.
Nat Commun. 2019 Jul 22;10(1):3268. doi: 10.1038/s41467-019-11211-y.
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 38-fold and 24-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.
Teixobactin 代表了一类新型抗生素，具有新颖的结构和针对革兰氏阳性病原体和结核分枝杆菌的优异活性。在此，我们报告了一种一锅反应，可方便地在 1 小时内以 30 克规模构建关键构建块 L-allo-Enduracidine，以及一种（3+2+6）的汇聚策略来完成泰索巴坦的克级全合成。描述了几种类似物，其中 20 和 26 被鉴定为最有效的类似物，与泰索巴坦相比，对万古霉素耐药粪肠球菌和耐甲氧西林金黄色葡萄球菌的效力分别提高了 38 倍和 24 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病小鼠模型和中性粒细胞减少症小鼠大腿感染模型中显示出高效性。我们还提出，泰索巴坦的反平行β-折叠对于其生物活性很重要，并且泰索巴坦的反平行二聚体通过关键氨基酸变化和分子对接是脂质 II 的最小结合单元。
