Generation of New-to-Nature Natural Products through Synthesis and Biosynthesis

This chapter describes the reader through recent applications of synthesis and the variations of synthetic biology and of synthetic chemistry blended with synthetic biology. It uses the two abbreviations Chem and Bio; the former refers to a chemical synthesis or partial chemical synthesis while the latter describes a biosynthesis or biological step. The chapter looks particularly at approaches that may be utilized to enable access to a series of analogues of natural products, with particular focus on natural products with antibiotic activities. Natural products are made by biomolecules and therefore naturally predisposed to interact with biomolecules; thus, as discussed above, they make an excellent starting point for drug discovery. Mutasynthesis enabling expansion of substrate scope is probably most clearly demonstrated for PKS and nonribosomal peptide synthetase biosynthetic pathways. Combinatorial biosynthesis, often referred to now as the synthetic biological modification of biosynthetic gene clusters, is the genetic manipulation of biosynthetic enzymes within or into a pathway.