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Erythromycins produced by  Saccharopolyspora erythraea  have broad-spectrum antibacterial activities. Recently, several TetR-family transcriptional regulators (TFRs) were identified to control erythromycin production by multiplex control modes; however, their regulatory network remains poorly understood. In this study, we report a novel TFR, SACE_0303, positively correlated with erythromycin production in  Sac. erythraea . It directly represses its adjacent gene  SACE_0304  encoding a MarR-family regulator and indirectly stimulates the erythromycin biosynthetic gene  eryAI  and resistance gene  ermE . SACE_0304 negatively regulates erythromycin biosynthesis by directly inhibiting  SACE_0303  as well as  eryAI  and indirectly repressing  ermE . Then, the SACE_0303 binding site within the  SACE_0303-SACE_0304  intergenic region was defined. Through genome scanning combined with  in vivo  and  in vitro  experiments, three additional SACE_0303 target genes ( SACE_2467  encoding cation-transporting ATPase,  SACE_3156  encoding a large transcriptional regulator,  SACE_5222  encoding α-ketoglutarate permease) were identified and proved to negatively affect erythromycin production. Finally, by coupling CRISPRi-based repression of those three targets with  SACE_0304  deletion and  SACE_0303  overexpression, we performed stepwise engineering of the SACE_0303-mediated mini-regulatory network in a high-yield strain, resulting in enhanced erythromycin production by 67%. In conclusion, the present study uncovered the regulatory network of a novel TFR for control of erythromycin production and provides a multiplex tactic to facilitate the engineering of industrial actinomycetes for yield improvement of antibiotics.

frontiers in bioengineering and biotechnology

Uncovering and Engineering a Mini-Regulatory Network of the TetR-Family Regulator SACE_0303 for Yield Improvement of Erythromycin in Saccharopolyspora erythraea