Omics-assisted systematic exploration of the intricate regulatory network of guvermectin biosynthesis centered by the cluster-situated regulator GvmR in Streptomyces

Guvermectin, produced by Streptomyces bacteria, is a purine nucleoside natural product recently registered as a new biopesticide to boost rice yield. Despite its importance, the regulatory network governing guvermectin biosynthesis remains largely unknown, severely impeding industrial-scale production and widespread application in rice production. Here, we investigated the diverse regulatory mechanisms employed by the cluster-situated regulatory gene, gvmR, in controlling guvermectin production from the perspective of widespread disturbance of gene expression at genome scale. GvmR activates the expression of guvermectin cluster by binding to the gvmR, gvmA and O1 promoters. Additionally, GvmR binds to the promoter of scnR1, a previously unidentified and highly conserved regulator in Streptomyces. scnR1 overexpression significantly suppressed guvermectin production by regulating the guvermectin cluster through binding to the same promoters as GvmR. Transcriptomic analysis revealed that GvmR extensively influences the expression of numerous genes located outside the guvermectin cluster, including the precursor supply (purine biosynthesis) and energy synthesis (oxidative phosphorylation) pathway genes, as well as 252 transcriptional regulatory genes. By genetic screening from 48 of these 252 regulatory genes, we identified additional five highly conserved genes that impact guvermectin production, suggesting a functional interplay between GvmR and highly conserved regulators in coordinating guvermectin production. These findings enrich our knowledge of the regulatory network governing guvermectin biosynthesis and offer a broadly applicable approach for investigating the molecular regulation of natural product biosynthesis and their high-titer production.