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

## TL;DR

A new regulator, ScnR1, was found to control guvermectin production in Streptomyces caniferus through competitive DNA binding and feedback inhibition.

## Contribution

Discovery of ScnR1's role in regulating guvermectin biosynthesis via competitive DNA binding and reciprocal feedback with GvmR2.

## Key findings

- ScnR1, a distant LacI-family regulator, suppresses guvermectin biosynthesis by binding to key promoters.
- ScnR1 and GvmR2 form a reciprocal feedback loop, each inhibiting the other's expression.
- This study reveals a multi-layered regulatory mechanism for guvermectin biosynthesis in Streptomyces.

## Abstract

Guvermectin, a Streptomyces-derived purine nucleoside, exhibits potent plant growth-promoting and broad-spectrum antibacterial activities, making it a promising agent for sustainable agriculture. Identification and characterization of novel transcriptional regulators involved in guvermectin biosynthesis is crucial for production improvement via transcriptional regulator engineering. This study identified ScnR1, an extra-cluster regulator influencing guvermectin production. The regulatory role of ScnR1 in guvermectin biosynthesis and its complex interactions with GvmR and GvmR2 were investigated. These findings advance our understanding of the multi-layered regulation of secondary metabolism in Streptomyces, offering a theoretical foundation for enhancing natural product yields through transcriptional regulator engineering.

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.