The Who, Why, and How of Small-Molecule Production in Invertebrate Microbiomes: Basic Insights Fueling Drug Discovery

Bacteria have supplied us with many bioactive molecules for use in medicine and agriculture. However, rates of discovery have decreased as the biosynthetic capacity of the culturable biosphere has been continuously mined for many decades. The as-yet-uncultured biosphere is likely to hold far greater biosynthetic potential, especially where ecological niches favor the selection of therapeutically useful bioactivities. I outline here how metagenomics and other systems biology approaches can be used to gain insight into small-molecule biosynthesis and the selective forces which shape it. I also argue that we need a greater understanding of the function of small molecules in complex microbiomes and rational synthetic biology methods to functionally reconstruct large biosynthetic pathways in heterologous hosts.