Discovery of Novel Phosphonate Natural Products and Their Biosynthetic Pathways by Large-Scale Genome Mining

Genome mining has revolutionized the field of natural products, providing hope that new antibiotics can be discovered in time before all remainders are rendered useless against multidrug resistant pathogens. While this approach has been successful in academic settings focused on small collections or individual strains, significant reinvestments in antibiotic discovery by the pharmaceutical industry would require validation that genome mining is superior for bioactive compound discovery compared to traditional methodologies. We initiated a large-scale genome mining driven campaign for phosphonate natural products, a diverse class of molecules with a history of successful commercialization into clinically used drugs and biotechnology products. High-throughput genome mining of 10,000 actinomycetes uncovered of an unprecedented diversity of phosphonate pathways contained within 300 strains. A comprehensive roadmap to new phosphonates was established based on a metabolic framework of their biosynthesis. Present are pathways for all known phosphonate natural products of bacterial origin with the exception of K-26 and I5B2, compounds whose biosynthesis is independent of phosphoenolpyruvate mutase. The trove of novel phosphonates encoded within the remaining pathways is estimated to be eight-fold greater than the total number of phosphonates identified in the 20^th century. Our campaign has discovered 15 new, chemically diverse phosphonate natural products thus far, including phosphonopeptides with broad-spectrum antibiotic activities and novel sulfur containing molecules. The success of this project demonstrates large-scale genome mining as a worthwhile endeavor for new antibiotic compounds. Additionally, we fulfill the promise of genomics-enabled drug discovery made 20 years earlier during the dawn of the whole-genome sequencing era.