Secondary metabolite induction by mycolic acid-containing bacteria in Streptomyces

Genome analyses are suggesting that single Streptomyces genome contains 20-40 cryptic secondary metabolite coding gene clusters. We are interested in development of methods to activate expression of those cryptic genes for efficient discovery of natural products. We have focused on the co-culture method, which may in part mimic the natural environment, for induction of antibiotic productions in Streptomyces, and found that bacteria within the suborder Corynebacterineae (e.g. Tsukamurella, Rhodococcus, Mycobacterium, Corynebacterium) can efficiently trigger the secondary metabolites production in Streptomyces.^1),2),3) Along with using this combined-culture method for discovery of new antibiotics, we are now investigating the activation mechanism of silent or poorly-expressed gene clusters of Streptomyces where in presence of the Corynebacterineae strains. Interesting phenomenon in this combined-culture is that, physical interaction between two strains seems to be required for activation of secondary metabolites induction in Streptomyces. When using the “small molecules diffusible” & “two culture separating” flask, we could not observe specific secondary metabolites production, eliminating the involvement of relatively understood diffusible small molecules (e.g.; second messengers, hormone-like substances, specific metabolites, or medium component changes) in their activation. Using microscopic strategy, we observed the physical adhesion of mycolic acid containing bacteria to the Streptomyces mycelia, supporting our prediction that physical contact may be an important trigger for the secondary metabolism activation in Streptomyces.

1) Onaka H. et al. Appl Environ Microbiol. 77(2), 2011

2) Igarashi Y. et al. Org Lett. 12(15), 2010

3) Hoshino S. et al. J Antibiot. 2014