Chapter 16 : New Molecules

Abstract:

This chapter talks about synthetic compound libraries and the new approaches with natural products as antibiotic candidates. It summarizes some recent efforts on reprogramming of biosynthetic assembly lines of polyketides (PKs) and nonribosomal peptides (NRPs) assembly lines and of the post-assembly-line enzymatic tailoring reactions to create new variants of natural products, “unnatural natural products." Carrying out combinatorial reprogramming on a large scale requires large numbers of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) gene clusters, an understanding of the rules for cutting and pasting to maximize autonomously folding modules, and rapid methods for gene shuffling. Some of the most intriguing natural products have five-ring sulfur and oxygen heterocycles, thiazoles, and oxazoles, which arise from cyclization of cysteinyl-SH and seryl-OH side chains on the preceding peptide bond carbonyl, catalyzed by cyclization (Cy) domains that are variants of the peptide bond-forming condensation domains. Reconstitution of PKS-NRPS and NRPS-PKS interfaces has been achieved with purified components in vitro to establish the recognition patterns of the KS, C, and Cy catalytic, chain-elongation domains, as a prelude to combinatorial strategies that would make novel hybrid PK-NRP-PK structures.