Abstract
Enediyne antibiotics epitomize nature's chemical creativity. They contain intricate molecular architectures that are coupled with potent biological activities involving double-stranded DNA scission. The recent explosion in microbial genome sequences has revealed a large reservoir of novel enediynes. However, while hundreds of enediyne biosynthetic gene clusters (BGCs) can be detected, less than two dozen natural products have been characterized to date as many clusters remain silent or sparingly expressed under standard laboratory growth conditions. This review focuses on four distinct strategies, which have recently enabled discoveries of novel enediynes: phenotypic screening from rare sources, biosynthetic manipulation, genomic signature-based PCR screening, and DNA-cleavage assays coupled with activation of silent BGCs via high-throughput elicitor screening. With an abundance of enediyne BGCs and emerging approaches for accessing them, new enediyne natural products and further insights into their biogenesis are imminent.