Manipulation of pathway regulation in Streptomyces globisporus for overproduction of the enediyne antitumor antibiotic C-1027

Manipulation of pathway regulation is an efficient strategy to increase specific secondary metabolite production. Here we successfully improved production of both the enediyne antitumor antibiotic C-1027 and a heptaebe, an early metabolite of the C-1027 pathway, by manipulating the three regulatory genes, sgcR1, sgcR2, and sgcR3, within the C-1027 biosynthetic gene cluster. SgcR3 has previously been established as an activator, and we now propose that SgcR1 and SgcR2 are also positive regulators based on their up-regulation effects on titer and/or timing of heptaene and C-1027 production in Streptomyces globisporus. Specifically, overexpression of sgcR1 significantly improved production of the heptaene (about 5-fold) and C-1027 (2- to 3-fold) compared to the wild-type strain. However, the titers of heptaene and C-1027 were not increased by overexpressing all three activators together, underscoring the complexity of C-1027 biosynthetic pathway regulation. The possibility of exploiting the heptaene as a readily identifiable and unique indicator for rapidly detecting enediyne production was also assessed.