Natural Products and Synthetic Biology: Where We Are and Where We Need To Go

Abstract

The biosynthetic talent of microorganisms has been harnessed for drug discovery for almost a century. Microbial metabolites not only account for the majority of antibiotics available today, but have also led to anticancer, immunosuppressant, and cholesterol-lowering drugs. Yet, inherent challenges of natural products-including inadequate supply and difficulties with structure diversification-contributed to their deprioritization as a source of pharmaceuticals. In recent years, advances in genome sequencing and synthetic biology spurred a renewed interest in natural products. Bacterial genomes encode an abundance of natural products awaiting discovery. Synthetic biology can facilitate not only discovery and improvements in supply, but also structure diversification. This perspective highlights prior accomplishments in the field of synthetic biology and natural products by the scientific community at large, including research from our laboratory. We also provide our opinion as to where we need to go to continue advancing the field.

Keywords: bacterial genomes; biosynthesis; drug discovery; metabolites; structure diversification.

FIG 1

Genomic, genetic, and synthetic biology approaches toward natural product drug discovery. (a) Exploration of bacteria from understudied environments and taxa follows the hypothesis that different selective pressures may lead to the evolution of distinct chemistry. Genomes are sequenced and biosynthetic gene clusters (BGCs) are identified using bioinformatic tools. (b) BGCs of interest are selected. Heterologous expression in suitable hosts can be used to streamline natural product discovery. Genome editing of native producers offers an alternative approach to aid discovery and to study gene and BGC function. (c) Pathway modification via BGC reprogramming contributes to structure diversification of natural products.