Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Angew Chem Int Ed Engl. 2022 Sep 26;61(39):e202208573. doi: 10.1002/anie.202208573. Epub 2022 Aug 19.
Natural products provide an important source of pharmaceuticals and chemical tools. Traditionally, assessment of unexplored microbial phyla has led to new natural products. However, with every new microbe, the number of orphan biosynthetic gene clusters (BGC) grows. As such, the more difficult proposition is finding new molecules from well-studied strains. Herein, we targeted Streptomyces rimosus, the widely-used oxytetracycline producer, for the discovery of new natural products. Using MALDI-MS-guided high-throughput elicitor screening (HiTES), we mapped the global secondary metabolome of S. rimosus and structurally characterized products of three cryptic BGCs, including momomycin, an unusual cyclic peptide natural product with backbone modifications and several non-canonical amino acids. We elucidated important aspects of its biosynthesis and evaluated its bioactivity. Our studies showcase HiTES as an effective approach for unearthing new chemical matter from "drained" strains.
天然产物为药物和化学工具提供了重要的来源。传统上，对未开发的微生物门的评估导致了新的天然产物的出现。然而，随着每一个新的微生物的出现，孤儿生物合成基因簇（BGC）的数量也在增加。因此，更困难的问题是从研究充分的菌株中寻找新的分子。在这里，我们选择了广为人知的土霉素生产菌——玫瑰色链霉菌，以发现新的天然产物。我们利用 MALDI-MS 引导的高通量诱导剂筛选（HiTES），绘制了 S.rimosus 的全球次级代谢组图谱，并对三个隐性 BGC 的产物进行了结构表征，其中包括莫米松，这是一种具有骨架修饰和几种非典型氨基酸的不寻常的环肽天然产物。我们阐明了其生物合成的重要方面，并评估了其生物活性。我们的研究表明，HiTES 是从“枯竭”菌株中挖掘新化学物质的有效方法。
