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Abstract:
The explosion of DNA sequence information and decreasing cost of DNA synthesis has enabled next-generation approaches to natural product discovery. In the human microbiome alone, thousands of molecules and enzymes are evidenced by DNA sequencing and computational annotation of gene clusters encoding their biosynthesis. However, “genome mining” such resources of molecular diversity requires targeted prospecting. Notably, macrocyclic natural products are estimated to account for 3% of known natural products but comprise 30% of recently approved unique natural product drugs (e.g. cyclosporine, echinocandin, daptomycin). Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a chemically diverse class of bioactive natural products enriched in macrocyclic scaffolds with potential therapeutic value. In this talk I will first describe a platform for standardized genome mining of RiPPs directly from DNA sequence data. This platform has enabled discovery of macrocyclic antimicrobials from the human microbiome with varied spectra of activity against other members of the microbiome as well as drug-resistant pathogens. I will then discuss how diverse RiPP modifying enzymes characterized via this approach can be combined with genetic selections to enrich and evolve new-to-nature macrocycles that bind therapeutic targets of interest. This technology has been applied to rapidly discover a thioether cross-linked peptide that targets the receptor binding domain of the SARS-CoV-2 Spike protein.