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Background  Lincomycin, produced by  Streptomyces lincolnensis , is a lincosamide antibiotic and widely used for the treatment of the infective diseases caused by Gram-positive bacteria. The mechanisms of lincomycin biosynthesis have been deeply explored in recent years. However, the regulatory effects of LmbU that is a transcriptional regulator in lincomycin biosynthetic ( lmb ) gene cluster have not been fully addressed.    Results  LmbU was used to search for homologous LmbU (LmbU-like) proteins in the genomes of actinobacteria, and the results showed that LmbU-like proteins are highly distributed regulators in the biosynthetic gene clusters (BGCs) of secondary metabolites or/and out of the BGCs in actinomycetes. The overexpression, inactivation and complementation of the  lmbU  gene indicated that LmbU positively controls lincomycin biosynthesis in  S. lincolnensis . Comparative transcriptomic analysis further revealed that LmbU activates the 28  lmb  genes at whole  lmb  cluster manner. Furthermore, LmbU represses the transcription of the non- lmb  gene  hpdA  in the biosynthesis of  l -tyrosine, the precursor of lincomycin. LmbU up-regulates nineteen non- lmb  genes, which would be involved in multi-drug flux to self-resistance, nitrate and sugar transmembrane transport and utilization, and redox metabolisms.    Conclusions  LmbU is a significant pleiotropic transcriptional regulator in lincomycin biosynthesis by entirely activating the  lmb  cluster and regulating the non- lmb  genes in  Streptomyces lincolnensis . Our results first revealed the pleiotropic regulatory function of LmbU, and shed new light on the transcriptional effects of LmbU-like family proteins on antibiotic biosynthesis in actinomycetes.

Comparative transcriptomic analysis reveals the significant pleiotropic regulatory effects of LmbU on lincomycin biosynthesis