Accessing the Hidden Majority of Marine Natural Products through Metagenomics

Tiny marine animals represent an untapped reservoir for undiscovered, bioactive natural products. However, their small size and extreme chemical variability preclude traditional chemical approaches to discovering new bioactive compounds. Here, we use a metagenomic method to directly discover and rapidly access cyanobactin class natural products from these variable samples, and provide proof-of-concept for genome-based discovery and supply of marine natural products. We also address practical optimization of complex, multistep ribosomal peptide pathways in heterologous hosts, which is still very challenging. The resulting methods and concepts will be applicable to ribosomal peptide and other biosynthetic pathways.