Recent Advances in Synthetic Biology Approaches to Optimize Production of Bioactive Natural Products in Actinobacteria

Abstract

Actinobacteria represent one of the most fertile sources for the discovery and development of natural products (NPs) with medicinal and industrial importance. However, production titers of actinobacterial NPs are usually low and require optimization for compound characterization and/or industrial production. In recent years, a wide variety of novel enabling technologies for engineering actinobacteria have been developed, which have greatly facilitated the optimization of NPs biosynthesis. In this review, we summarize the recent advances of synthetic biology approaches for overproducing desired drugs, as well as for the discovery of novel NPs in actinobacteria, including dynamic metabolic regulation based on metabolite-responsive promoters or biosensors, multi-copy chromosomal integration of target biosynthetic gene clusters (BGCs), promoter engineering-mediated rational BGC refactoring, and construction of genome-minimized Streptomyces hosts. Integrated with metabolic engineering strategies developed previously, these novel enabling technologies promise to facilitate industrial strain improvement process and genome mining studies for years to come.

Keywords: BGC amplification; actinobacteria; dynamic regulation; genome-minimized host; natural product; pathway refactoring; synthetic biology.