Combined induction: effective fermentation procedure for heterologous secondary metabolite production in actinomycetes

Introduction. The members of the order Actinomycetes, especially the genus Streptomyces, have the potential to produce many antibiotics and bioactive natural compounds. A recent analysis of the Streptomyces genome revealed the presence of almost 30 biosynthetic gene clusters for secondary metabolite production, and these data imply that a single strain of Streptomyces can produce over 30 secondary metabolites. However, most of these secondary metabolites cannot be isolated from the broth of Streptomyces pure culture. To date, various methods have been used to induce these “silent” genes biosynthesizing the secondary metabolites. Combined culture method is a co-culture method used to activate such silent genes. When mycolic acid-containing bacteria (MACB) were co-cultured with Streptomyces, MACB induced secondary metabolisms in Streptomyces, and the profiles of secondary metabolites changed (1). We used this finding to develop a new coculture method called the “combined culture” and discovered new antibiotics, Alchivemycins from Streptomyces endus S-522 (2). Here, we will show "combined induction" method, that is, the combined culture method can be applied to develop a heterologous expression host to increase the production of antibiotics.