Molecular Biotechnology, Institute of Biology, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands.
Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA.
Sci Rep. 2022 Feb 18;12(1):2813. doi: 10.1038/s41598-022-06736-0.
Streptomycetes are major producers of bioactive natural products, including the majority of the naturally produced antibiotics. While much of the low-hanging fruit has been discovered, it is predicted that less than 5% of the chemical space of natural products has been mined. Here, we describe the discovery of the novel actinomycins L and L produced by Streptomyces sp. MBT27, via application of metabolic analysis and molecular networking. Actinomycins L and L are diastereomers, and the structure of actinomycin L was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X prior to the condensation of the actinomycin halves. Such a structural feature has not previously been identified in naturally occurring actinomycins. Adding anthranilamide to cultures of the actinomycin X producer Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27, resulted in the production of actinomycin L. This supports a biosynthetic pathway whereby actinomycin L is produced from two distinct metabolic routes, namely those for actinomycin X and for anthranilamide. Actinomycins L and L showed significant antimicrobial activity against Gram-positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.
链霉菌是生物活性天然产物的主要生产者，包括大多数天然产生的抗生素。虽然已经发现了很多容易发现的成果，但预计只有不到 5%的天然产物化学空间被挖掘出来。在这里，我们描述了通过代谢分析和分子网络应用发现的新型链霉菌 MB T27 产生的放线菌素 L 和 L。放线菌素 L 和 L 是差向异构体，放线菌素 L 的结构通过 NMR 和单晶 X 射线晶体学解析得到解决。放线菌素 L 是通过前体放线菌素 X 的 4-氧脯氨酸部分与蒽酰胺的螺环连接，然后再进行放线菌素半缩合形成的。这种结构特征以前在天然存在的放线菌素中没有被识别过。向具有与 MB T27 相同生物合成基因簇的放线菌素 X 产生菌 Streptomyces antibioticus 的培养物中添加蒽酰胺，会导致放线菌素 L 的产生。这支持了一种生物合成途径，即放线菌素 L 是由两条不同的代谢途径产生的，即放线菌素 X 和蒽酰胺的途径。放线菌素 L 和 L 对革兰氏阳性菌表现出显著的抗菌活性。我们的工作表明，即使是在最古老的天然产物家族中，仍然可以识别出新的分子。
