Department of Chemistry, University of Zurich, 8057, Zürich, Switzerland.
Department of Microbial Physiology and Molecular Biology, Institute of Microbiology, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany.
Chembiochem. 2023 Dec 14;24(24):e202300570. doi: 10.1002/cbic.202300570. Epub 2023 Oct 9.
Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram-positive bacteria such as Mycobacterium tuberculosis. Only a few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well-studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram-negative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho-methyl Fdx also exhibited activity against the Gram-negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next-generation fidaxomicin antibiotics.
非达霉素（Fdx）是一种天然产物抗生素，对艰难梭菌和结核分枝杆菌等其他革兰氏阳性菌具有很强的活性。自发现以来的 50 年里，只有少数 Fdx 衍生物被合成并研究其生物活性。Fdx 的作用机制研究得很透彻，即抑制细菌 RNA 聚合酶。然而，靶向生物具有不同的靶蛋白序列，这给新的半合成 Fdx 衍生物的合理开发带来了挑战。我们在 Fdx 的两个酚羟基上引入取代基，并评估了它们对结核分枝杆菌、艰难梭菌和革兰氏阴性模式生物新月柄杆菌的抗生素活性的变化趋势。根据靶蛋白结构，我们确定了每个生物的首选衍生化部位。邻甲基 Fdx 衍生物也对革兰氏阴性的新月柄杆菌野生型具有活性，这是第一个对非达霉素抗生素具有活性的例子。这些见解将指导下一代非达霉素抗生素的合成。
