Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer Streptomyces rimosus

• Published in: Angewandte Chemie Vol. 134; no. 39
• Main Authors: Li, Yuchen, Lee, Seoung Rak, Han, Esther J., Seyedsayamdost, Mohammad R.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 26.09.2022
• Subjects: Amino acids; Biological activity; Biosynthesis; Chemistry; Cryptic Metabolites; Gene clusters; HiTES; Metabolites; Microorganisms; Natural Products; Non-Ribosomal Peptides; Oxytetracycline; Streptomyces rimosus
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202208573

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. Microbial producers of pharmaceuticals still code for dozens of yet‐to‐be identified natural products. Herein, three groups of cryptic metabolites were uncovered from Streptomyces rimosus, the industrial producer of oxytetracycline, using high‐throughput elicitor screening, notably momomycin, a novel cyclic peptide with antiproliferative properties.