Genome mining of rare actinomycetes and cryptic pathway awakening

• Novel natural products are now coming from the non-Streptomyces rare actinomycetes.
• Significant numbers of their biosynthetic gene clusters turn out to silent or cryptic.
• Genome mining with cryptic pathway awakening identifies novel or weakly produced compounds.
• We discuss biotechnological potential of rare actinomycetes as natural product storehouses.
• We discuss examples on rare actinomycetes genome mining and cryptic pathway awakening.

Actinomycetes have been major storehouse microorganisms for the discovery of natural products in the last several decades. Although many of the discovered natural products have been successfully isolated from the most dominant actinomycetes genus, Streptomyces, novel natural products are increasingly coming from the non-Streptomyces family, known as rare actinomycetes. Moreover, some of the natural-product biosynthetic gene clusters in actinomycetes are silent or cryptic, meaning that the gene clusters are not expressed under typical laboratory culture conditions. Accordingly, genome mining has become a widely practiced alternative way to identify potentially valuable cryptic natural products from actinomycetes. Unlike the many advances in Streptomyces genomes mining, however, relatively few genome mining cases are available in rare actinomycetes. In this mini review, we discuss the biotechnological potential of rare actinomycetes as natural product storehouses, followed by a survey of the natural products that have been identified through the traditional processes of actinomycete screening. We focus in depth on several known examples of novel secondary metabolites as identified through the genome mining of rare actinomycetes. In addition, various approaches that have been applied in awakening techniques for actinomycete cryptic metabolite pathways are summarized.