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Background Subtilin is a peptide antibiotic (lantibiotic) natively produced by  Bacillus subtilis  ATCC6633. It is encoded in a gene cluster  spaBTCSIFEGRK  ( spa -locus) consisting of four transcriptional units:  spaS  (subtilin pre-peptide),  spaBTC  (modification and export),  spaIFEG  (immunity) and  spaRK  (regulation). Despite the pioneer understanding on subtilin biosynthesis, a robust platform to facilitate subtilin research and improve subtilin production is still a poorly explored spot. Results In this work, the intact  spa -locus was successfully integrated into the chromosome of  Bacillus subtilis  W168, which is the by far best-characterized Gram-positive model organism with powerful genetics and many advantages in industrial use. Through systematic analysis of  spa -promoter activities in  B. subtilis  W168 wild type and mutant strains, our work demonstrates that subtilin is basally expressed in  B. subtilis  W168, and the transition state regulator AbrB strongly represses subtilin biosynthesis in a growth phase-dependent manner. The deletion of AbrB remarkably enhanced subtilin gene expression, resulting in comparable yield of bioactive subtilin production as for  B. subtilis  ATCC6633. However, while in  B. subtilis  ATCC6633 AbrB regulates subtilin gene expression via SigH, which in turn activates  spaRK,  AbrB of  B. subtilis  W168 controls subtilin gene expression in SigH-independent manner, except for the regulation of  spaBTC . Furthermore, the work shows that subtilin biosynthesis in  B. subtilis  W168 is regulated by the two-component regulatory system SpaRK and strictly relies on subtilin itself as inducer to fulfill the autoregulatory circuit. In addition, by incorporating the subtilin-producing system ( spa -locus) and subtilin-reporting system (P  psdA  - lux ) together, we developed “online” reporter strains to efficiently monitor the dynamics of subtilin biosynthesis. Conclusions Within this study, the model organism  B. subtilis  W168 was successfully established as a novel platform for subtilin biosynthesis and the underlying regulatory mechanism was comprehensively characterized. This work will not only facilitate genetic (engineering) studies on subtilin, but also pave the way for its industrial production. More broadly, this work will shed new light on the heterologous production of other lantibiotics.

Regulation of heterologous subtilin production in Bacillus subtilis W168