Targeted Discovery of Cryptic Enediyne Natural Products via FRET-Coupled High-Throughput Elicitor Screening

Esther J. Han, Seoung Rak Lee, Craig A. Townsend, Mohammad R. Seyedsayamdost

Research output: Contribution to journalArticlepeer-review

Abstract

Enediyne antibiotics are a striking family of DNA-cleaving natural products with high degrees of cytotoxicity and structural complexity. Microbial genome sequences, which have recently accumulated, point to an untapped trove of “cryptic” enediynes. Most of the cognate biosynthetic gene clusters (BGCs) are sparingly expressed under standard growth conditions, making it difficult to characterize their products. Herein, we report a fluorescence-based DNA cleavage assay coupled with high-throughput elicitor screening for the rapid, targeted discovery of cryptic enediyne metabolites. We applied the approach to Streptomyces clavuligerus, which harbors two such BGCs with unknown products, identified steroids as effective elicitors, and characterized 10 cryptic enediyne-derived natural products, termed clavulynes A-J with unusual carbonate and terminal olefin functionalities, with one of these congeners matching the recently reported jejucarboside. Our results contribute to the growing repertoire of enediynes and provide a blueprint for identifying additional ones in the future.

Original languageEnglish (US)
Pages (from-to)1854-1862
Number of pages9
JournalACS chemical biology
Volume18
Issue number8
DOIs
StatePublished - Aug 18 2023

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

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