Chemical Metagenomics of an Anti-HIV Compound From Uncultivated Symbionts

Microbial symbionts in humans, animals, and plants are unparalleled sources of compounds for drug discovery. However, methods are needed to access natural biodiversity and make it amenable to pharmaceutical and biotechnological development. Here, we employ a novel approach marrying traditional natural products chemistry with modern metagenomics and synthetic biology in Escherichia coli to discover, synthesize, and analogue divamides, anti‐HIV molecules from rare coral reef animals. We demonstrate that divamides are produced by Prochloron symbiotic bacteria, which have eluded cultivation for >40 years. This represents a new paradigm of direct compound discovery from a true symbiotic relationship. We show that the divamides arise from a diversitygenerating biosynthetic pathway, which was exploited to generate derivatives for mechanism of action studies. The synthesis of closely related, yet functionally distinct compounds by a single biosynthetic pathway provides the first direct evidence supporting the "speculative metabolism" hypothesis of chemical diversity.