Dailler David, Dorst Andrea, Schäfle Daniel, Sander Peter, Gademann Karl
Department of Chemistry, University of Zurich, Zurich, Switzerland.
Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland.
Commun Chem. 2021 May 10;4(1):59. doi: 10.1038/s42004-021-00501-6.
Fidaxomicin (FDX) is a marketed antibiotic for the treatment of Clostridioides difficile infections (CDI). Fidaxomicin displays antibacterial properties against many Gram-positive bacteria, yet the application of this antibiotic is currently limited to treatment of CDI. Semisynthetic modifications present a promising strategy to improve its pharmacokinetic properties and also circumvent resistance development by broadening the structural diversity of the derivatives. Here, based on a rational design using cryo-EM structural analysis, we implement two strategic site-selective catalytic reactions with a special emphasis to study the role of the carbohydrate units. Site-selective introduction of various ester moieties on the noviose as well as a Tsuji-Trost type rhamnose cleavage allow the synthesis of novel fidaxomicin analogs with promising antibacterial activities against C. difficile and Mycobacterium tuberculosis.
非达霉素（FDX）是一种已上市的用于治疗艰难梭菌感染（CDI）的抗生素。非达霉素对许多革兰氏阳性菌具有抗菌特性，但这种抗生素目前仅限于用于治疗CDI。半合成修饰是一种很有前景的策略，可改善其药代动力学性质，还能通过拓宽衍生物的结构多样性来规避耐药性的产生。在此，基于使用冷冻电镜结构分析的合理设计，我们实施了两个策略性的位点选择性催化反应，特别着重研究碳水化合物单元的作用。在新霉糖上位点选择性引入各种酯基以及进行Tsuji-Trost型鼠李糖裂解，从而合成出了对艰难梭菌和结核分枝杆菌具有良好抗菌活性的新型非达霉素类似物。
