ScnR1-Mediated Competitive DNA Binding and Feedback Inhibition Regulate Guvermectin Biosynthesis in Streptomyces caniferus

Guvermectin, a Streptomyces-derived purine nucleoside compound, exhibits dual bioactivities as a plant growth regulator and an antibacterial agent. While its biosynthetic gene cluster (BGC) is regulated by the cluster-situated activator GvmR and the adjacent repressor GvmR2, the role of distal transcriptional regulators (TRs) in guvermectin biosynthesis remains unexplored. Here, we identified ScnR1, a highly conserved LacI-family TR located far from the guvermectin BGC, which is directly activated by GvmR. Overexpression of scnR1 significantly suppressed guvermectin biosynthesis. Further investigations revealed that ScnR1 competitively binds to the gvmR, gvmA, and O1 promoters (overlapping with the GvmR-binding sites), thereby inhibiting the guvermectin BGC transcription. Moreover, ScnR1 formed a reciprocal feedback loop with the adjacent repressor GvmR2, where each repressor inhibits the other’s expression. These findings reveal a multi-layered regulatory mechanism wherein LacI-family TRs fine-tune guvermectin biosynthesis through competitive DNA binding and reciprocal feedback control. This study offers new perspectives on the hierarchical control of secondary metabolism in Streptomyces and provides valuable theoretical guidance for the engineering of strains with enhanced natural product production.