Manipulation and epigenetic control of silent biosynthetic pathways in actinobacteria

Most biosynthetic gene clusters (BGCs) of Actinobacteria are either silent or expressed less than the detectable level. The non-genetic approaches including biological interactions, chemical agents, and physical stresses that can be used to awaken silenced pathways are compared in this paper. These non-genetic induction strategies often need screening approaches, including one strain many compounds (OSMAC), reporter-guided mutant selection, and high throughput elicitor screening (HiTES) have been developed. Different types of genetic manipulations applied in the induction of cryptic BGCs of Actinobacteria can be categorized as genome-wide pleiotropic and targeted approaches like manipulation of global regulatory systems, modulation of regulatory genes, ribosome and engineering of RNA polymerase or phosphopantheteine transferases. Targeted approaches including genome editing by CRISPR, mutation in transcription factors and modification of BGCs promoters, inactivation of the highly expressed biosynthetic pathways, deleting the suppressors or awakening the activators, heterologous expression, or refactoring of gene clusters can be applied for activation of pathways which are predicted to synthesize new bioactive structures in genome mining studies of Acinobacteria. In this review, the challenges and advantages of employing these approaches in induction of Actinobacteria BGCs are discussed. Further, novel natural products needed as drug for pharmaceutical industry or as biofertilizers in agricultural industry can be discovered even from known species of Actinobactera by the innovative approaches of metabolite biosynthesis elicitation.