Automated, self-resistance gene-guided, and high-throughput genome mining of bioactive natural products from Streptomyces

Natural products (NPs) produced by bacteria, fungi and plants are a major source of drug leads. Streptomyces species are particularly important in this regard as they produce numerous natural products with prominent bioactivities. Here we report a fully automated, scalable and high-throughput platform for discovery of bioactive natural products in Streptomyces (FAST-NPS). This platform comprises computational prediction and prioritization of target biosynthetic gene clusters (BGCs) guided by self-resistance genes, highly efficient and automated direct cloning and heterologous expression of BGCs, followed by high-throughput fermentation and product extraction from Streptomyces strains. As a proof of concept, we applied this platform to clone 105 BGCs ranging from 10 to 100 kb that contain potential self-resistance genes from 11 Streptomyces strains with a success rate of 95%. Heterologous expression of all successfully cloned BGCs in Streptomyces lividans TK24 led to the discovery of 23 natural products from 12 BGCs. We selected 5 of these 12 BGCs for further characterization and found each of them could produce at least one natural product with antibacterial and/or anti-tumor activity, which resulted in a total of 8 bioactive natural products. Overall, this work would greatly accelerate the discovery of bioactive natural products for biomedical and biotechnological applications. Graphic Abstracts O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/564101v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@11068c9org.highwire.dtl.DTLVardef@4f68c5org.highwire.dtl.DTLVardef@16767edorg.highwire.dtl.DTLVardef@1d82eab_HPS_FORMAT_FIGEXP M_FIG C_FIG