Expediting natural product discovery through genomics

Abstract

Natural product chemicals have historically been discovered based on their molecular and biological properties. With the ease and affordability of genome sequencing today, a new era in natural product discovery is unfolding in which genomics and biosynthesis are together fostering new innovations in compound discovery. This orthogonal discovery approach takes advantage of the biosynthetic potential of a genome-sequenced organism to design hypothesis-driven experiments to uncover new chemical entities. Realizing that mass spectrometry-induced fragmentation of peptidic and carbohydrate-based molecules yields amino acid and sugar monomers that directly correlate as biosynthetic building blocks, we developed two complementary mass spectrometry-guided genome mining methods that connect diverse peptides and sugar-based metabolites directly to their biosynthetic gene clusters. In this lecture I will introduce peptidogenomics (Nat. Chem. Biol., 7, 794–802, 2011) and glycosogenomics as powerful new discovery methods that iteratively match de novo MSn structures to genomics-based structures following current biosynthetic logic. Several novel microbial natural products will be presented to illustrate the unbiased flexibility of this concept that has the potential for automating the genome mining process.