| Summary: | <i>Streptomyces</i> spp. are prolific sources of valuable natural products (NPs) that are of great interest in pharmaceutical industries such as antibiotics, anticancer chemotherapeutics, immunosuppressants, etc. Approximately two-thirds of all known antibiotics are produced by actinomycetes, most predominantly by <i>Streptomyces</i>. Nevertheless, in recent years, the chances of the discovery of novel and bioactive compounds from <i>Streptomyces</i> have significantly declined. The major hindrance for obtaining such bioactive compounds from <i>Streptomyces</i> is that most of the compounds are not produced in significant titers, or the biosynthetic gene clusters (BGCs) are cryptic. The rapid development of genome sequencing has provided access to a tremendous number of NP-BGCs embedded in the microbial genomes. In addition, the studies of metabolomics provide a portfolio of entire metabolites produced from the strain of interest. Therefore, through the integrated approaches of different-omics techniques, the connection between gene expression and metabolism can be established. Hence, in this review we summarized recent advancements in strategies for activating cryptic BGCs in <i>Streptomyces</i> by utilizing diverse state-of-the-art techniques.
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