Antibiotic biosynthesis in actinomycetes is controlled by various transcription factors, with TetR family regulators (TFRs) serving as important modulators of this process. We previously discovered a TFR, SACE₁906, which hinders erythromycin yield in Saccharopolyspora erythraea. However, the precise mechanism by which SACE₁906 regulates erythromycin biosynthesis remains elusive. Herein, we confirmed that SACE₁906 directly inhibits the transcription of its own and neighboring alcohol dehydrogenase gene SACE₁905, as well as all genes within the erythromycin biosynthetic cluster. It was found that two identical conserved sites (5'-CACCGGTCGGTATA-3') in the intergenic spacer between SACE₁905 and SACE₁906 (SACE₁905-1906-int) are necessary for SACE₁906 binding. Deletion of SACE₁906 resulted in decreased propionyl-CoA content but increased the intracellular supply of methylmalonyl-CoA. We further proved that SACE₁906 restricts methylmalonyl-CoA production from propionyl-CoA to influence intracellular levels of these two erythromycin biosynthetic precursors through the direct repression of several propionyl-CoA carboxylase genes. Moreover, acetaldehyde has been characterized as an effector molecule of SACE₁906 that weakens its binding affinity for SACE₁905-1906-int. This study reveals a novel mechanism by which SACE₁906 orchestrates erythromycin biosynthesis in response to acetaldehyde, expanding our understanding of small-molecule-mediated regulation for antibiotic biosynthesis in actinomycetes.
Wu et al. (Tue,) studied this question.