https://doi.org/10.1016/j.ijbiomac.2025.143161，International Journal of Biological Macromolecules，2025

ABSTRACT

DeoR family transcriptional regulators are widely distributed in Streptomyces genomes, but their precise functions and regulatory mechanisms in secondary metabolite biosynthesis remain poorly understood. In Streptomyces bingchenggensis, an industrial producer of milbemycins and  nanchangmycin, we identified the DeoR-type regulator SbhR as a key regulator of the atypical two-component system AtcK/R. CRISPR interference-mediated inhibition of sbhR significantly decreased milbemycin production but enhanced nanchangmycin production. SbhR was shown to activate atcK expression, thereby initiating the AtcK/R-KelR cascade that regulates both milbemycin and nanchangmycin biosynthesis. In strains with inhibited sbhR or atcK, AtcR was found to exert a positive effect on nanchangmycin production, in contrast to its inhibitory role observed in BC04. Through integrated overexpression of atcR and the cluster-situated activators nanR1 and nanR2 in sbhR- and atcK-repressed strains, nanchangmycin production was enhanced from 1060 mg/L to 8812 mg/L and 9675 mg/L, respectively, and the fermentation time required to reach maximum titer was reduced from 9 to 6 days. Cross-species genetic analyses further demonstrated that SbhR functions as a global regulatory switch for secondary metabolism in Streptomyces species. These results expand our understanding of the regulatory networks governing secondary metabolism and provide novel strategies for enhancing the yield of valuable metabolites in Streptomyces.

International Journal of Biological Macromolecules，IF=8.5

https://www.sciencedirect.com/science/article/pii/S0141813025037134?via%3Dihub