Mycolic acid-containing bacteria activate heterologous secondary metabolite expression in Streptomyces lividans

The Journal of Antibiotics
2015.0

Abstract

Streptomyces species possess 30–40 secondary metabolite biosynthetic gene clusters, yet most are silent or expressed at undetectable levels under pure culture conditions. Heterologous expression of these clusters in hosts like Streptomyces lividans often yields insufficient production. Previously, we found that mycolic acid-containing bacteria can induce secondary metabolism in Streptomyces via physical contact, a strategy we termed "combined culture." Here, we investigated the utility of combined culture to enhance heterologous metabolite production in S. lividans using the biosynthetic gene clusters of goadsporin (a ribosomally synthesized and post-translationally modified peptide), staurosporine (a potent protein kinase C inhibitor), and rebeccamycin (a DNA topoisomerase I inhibitor). We found that combined culture of S. lividans heterologous strains with mycolic acid-containing bacteria (Tsukamurella pulmonis, Rhodococcus erythropolis, or Corynebacterium glutamicum) dramatically increased the yields of these bioactive compounds compared to pure culture. For instance, staurosporine production in pure culture was only 0.6 mg/l, while combined culture with T. pulmonis achieved 104 mg/l (a 200-fold increase). Goadsporin production reached 408 mg/l in combined culture with T. pulmonis, and rebeccamycin yields were also significantly elevated. Our results demonstrate that combined culture is an effective method to boost heterologous secondary metabolite production in S. lividans. This approach, which requires no complex genetic manipulation or chemical inducers, holds promise for activating silent gene clusters and facilitating the discovery and production of diverse secondary metabolites.

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