Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, 510632, People's Republic of China.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Nat Commun. 2017 Nov 21;8(1):1644. doi: 10.1038/s41467-017-01813-9.
Fusidane-type antibiotics represented by helvolic acid, fusidic acid and cephalosporin P are a class of bacteriostatic agents, which have drawn renewed attention because they have no cross-resistance to commonly used antibiotics. However, their biosynthesis is poorly understood. Here, we perform a stepwise introduction of the nine genes from the proposed gene cluster for helvolic acid into Aspergillus oryzae NSAR1, which enables us to isolate helvolic acid (~20 mg L) and its 21 derivatives. Anti-Staphylococcus aureus assay reveals that the antibacterial activity of three intermediates is even stronger than that of helvolic acid. Notably, we observe an unusual C-4 demethylation process mediated by a promiscuous short-chain dehydrogenase/reductase (HelC) and a cytochrome P450 enzyme (HelB1), which is distinct from the common sterol biosynthesis. These studies have set the stage for using biosynthetic approaches to expand chemical diversity of fusidane-type antibiotics.
以海扶酸、夫西地酸和头孢菌素 P 为代表的 Fusidane 型抗生素是一类抑菌剂，由于它们与常用抗生素没有交叉耐药性，因此引起了人们的重新关注。然而，它们的生物合成过程还不太清楚。在这里，我们逐步将海扶酸的九个基因从提出的基因簇中引入米曲霉 NSAR1，这使我们能够分离出海扶酸（~20mg/L）及其 21 种衍生物。抗金黄色葡萄球菌测定表明，三种中间体的抗菌活性甚至强于海扶酸。值得注意的是，我们观察到一种不寻常的 C-4 去甲基化过程，该过程由一种混杂的短链脱氢酶/还原酶（HelC）和细胞色素 P450 酶（HelB1）介导，与常见的固醇生物合成不同。这些研究为利用生物合成方法扩展 Fusidane 型抗生素的化学多样性奠定了基础。
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