Synthetic Biology for Discovery and Production of Anti-Microbial Drugs

Microorganisms naturally produce many pharmaceutically and industrially relevant secondary metabolites. For this process they usually use biosynthetic units. For example, microbes from the genus Streptomyces possess great ability to produce a variety of natural products in such manner, which is possible due to complicated crosstalk between primary and secondary metabolism. These microbial cell factories produce more than 2/3 of antibiotics used in medicine, and a large variety of other bioactive compounds. Although bacterial producer hosts, including Bacillus spp. and Streptomyces spp., have been studied for decades, the engineering of these bacteria remains challenging, and the genetic potential has not been fully utilized. This is due to limited genetic toolbox, restriction activity and occurrence of silent biosynthetic gene clusters. Recent advancements in genetic manipulation of microorganisms allowed to improve 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. Synthetic biology has emerged as a robust strategy to understand, investigate, design, and engineer the biosynthetic capability of bacterial antibiotics machinery, including such in Streptomyces. Innovative synthetic biology and metabolic engineering tools have rapidly accelerated the discovery of new natural products as well as engineering of Streptomyces, e.g. enzymatic modules for secondary metabolite production can be combined in synthetic cells to produce new derivatives of natural products. Furthermore, with the recent advances in molecular biology and genome editing, Synthetic biology has focused at generation of controlled phenotypes from a given input and at other sophisticated approaches. In this review, developments of novel approaches of Synthetic biology for microbial engineering with focus on antibiotics producers like Streptomyces spp. are discussed.