Synthetic Biology Approaches for Engineering of Secondary Metabolism in Streptomyces: Manipulation of Crosstalk between Primary and Secondary Metabolism

Organisms from the genus Streptomyces feature actinobacteria with complex developmental cycle and great ability to produce a variety of natural products, which is possible due to complicated crosstalk between primary and secondary metabolism. These soil bacteria produce more than 2/3 of antibiotics used in medicine, and a large variety of bioactive compounds for industry and agricultural use. Although Streptomyces spp. have been studied for decades, the engineering of these bacteria remains challenging, and available genetic tools rather limited. Recent advancements in genetic manipulation of Streptomyces involving proposal of CRISPR/Cas9-based workflows as well as synthetic components (e.g. promoters, ribosome-binding sites, terminators, reporter genes) allowed to facilitate the turnaround time of strain engineering, but still has strain-specific limitations. However, a new perspective offered by synthetic biology to exploit the potential of existing and novel pathways in primary and secondary metabolism allows combining of different biosynthetic steps originating from diverse bacteria using a limited toolbox. Manipulation of interplay between primary and secondary metabolism proposes strategies to overcome strain-specific difficulties in engineering, leveraging insights in Streptomyces-specific physiological features. In this review, developments of these approaches for Streptomyces engineering are discussed and an overview of the synthetic biology developments is provided.