Metagenome Driven Discovery of Nonribosomal Peptides

Declining rates of novel natural product discovery and exponential rates of rediscovery heralded the end of the 1940s to 1960s "golden era" of antibiotic discovery. Fifty years later, the implementation of molecular screening methodologies revealed that standard culture-based screening approaches had failed to capture the vast majority of environmental bacteria and that even for the cultivable isolates only a small fraction of the biosynthetic potential had been tapped. A diversity of metagenomic screening and synthetic biology approaches have been developed to address these issues. The nonribosomal peptides have received particular focus, owing to their high levels of bioactivity and the predictability of the biosynthetic logic of the genetically encoded assembly lines that produce them. By uniting advances in next-generation sequencing and bioinformatic analysis with a diversity of traditional disciplines, several pioneering teams have proven that this previously inaccessible resource is no longer out of reach.