Plasmodium-Resistant Indole Diterpenoid Biosynthesis Gene Cluster Derived from Aspergillus oryzae Was Activated by Exogenous P450 Gene Ast B

作者：Wencong Yang, Tao Chen, Qi Tan, Zhenming Zang, Yan Chen, Yanghui Ou, Gang Li, Dan Hu, Bo Wang, Hongliang Yao, Zhigang She · 发表于：Journal of Natural Products · 年份：2023 · DOI：10.1021/acs.jnatprod.2c01172 · 被引用次数：15 · 研究领域：Microbial Natural Products and Biosynthesis、Plant biochemistry and biosynthesis、Computational Drug Discovery Methods

Synthetic biology is an effective way to activate silent biosynthetic gene clusters. Five new indole diterpenoids ( 1, 2, 5, 9, and 10 ), together with 10 known derivatives ( 3, 4, 6 – 8, and 11 – 15 ) were activated from Aspergillus oryzae transformants by an exogenous P450 gene Ast B and obtained under the guidance of molecular networking. Their planar structures were determined by NMR and HR-ESI-MS. The absolute configuration of compound 1 was determined by single crystal X-ray diffraction, and those of compounds 2, 5, 9, and 10 were confirmed by comparing the observed ECD with the calculated ECD. HPLC analysis suggested that the BGCs of indole diterpenoids in A. oryzae were activated by exogenous P450 gene Ast B . Compounds 1 – 4, 7, 8, and 11 displayed strong activity against chloroquine-sensitive plasmodium strain P.f. 3D7 with IC 50 values ranging from 0.84 to 2.9 μM. It is the first report that indole diterpenoids have potential antimalarial activity. The structure–activity relationship study showed that the linear indole diterpenoids contribute significantly to the antiparasite activity. Molecular docking studies showed that 1 and positive control chloroquine were at the center of the active pocket of Pf Hsp90, while 11 was far from the active site.