Disruption of negative regulators (SP_nsdA and SP_nsdB) in Streptomyces peucetius causes doxorubicin overproduction

Pathway-specific regulatory genes generally participate in the secondary metabolites-related biosynthesis process. The genes nsdA and nsdB were reported to have a negative effect on the production of actinorhodin, prodigiosin and calcium-dependent antibiotic from Streptomyces coelicolor. In this study, we searched for similar genes in the Streptomyces peucetius genome, the doxorubicin producer. Amino acid sequence similarity between SC_NsdA and SP4635 (SP_NsdA) was 88.1%, and between SC_NsdB and SP1750 (SP_NsdB) was 78.4%. High performance liquid chromatography (HPLC) analysis revealed that the disruption of SP_nsdA and SP_nsdB significantly increased doxorubicin production by 2.07 and 1.74-fold, respectively. The SP_nsdA and SP_nsdB disruption mutants produced more yellow pigment and early aerial mycelium than did the original wild-type strain. These results show that SP_nsdA and SP_nsdB negatively affected doxorubicin production and morphological differentiation in S. peucetius.