Improved production of antifungal angucycline Sch47554 by manipulating three regulatory genes in Streptomyces sp. SCC-2136.

Sch47554 and Sch47555 are two angucyclines with antifungal activities against various yeasts and dermatophytes from Streptomyces sp. SCC-2136. The sch gene cluster contains several putative regulatory genes. Both schA4 and schA21 were predicted as the TetR family transcriptional regulators, whereas schA16 shared significant similarity to the AraC family transcriptional regulators. Although Sch47554 is the major product of Streptomyces sp. SCC-2136, its titer is only 6.72 mg/L. This work aimed to increase the production of this promising antifungal compound by investigating and manipulating the regulatory genes in the Sch47554 biosynthetic pathway. Disruption of schA4 and schA16 led to a significant increase in the production of Sch47554, whereas the titer was dramatically decreased when schA21 was disrupted. Overexpression of these genes gave opposite results. The highest titer of Sch47554 was achieved in Streptomyces sp. SCC-2136/ΔschA4 (27.94 mg/L), which is significantly higher than the wild type. Our results indicate that SchA4 and SchA16 are repressors, whereas SchA21 acts as an activator. This work thus provides an initial understanding of functional roles of regulatory elements in the biosynthesis of Sch47554. Several efficient producing strains of Sch47554 were constructed by disrupting or overexpressing particular regulatory genes, which can be further engineered for industrial production of this medicinally important molecule.