Abstract
Actinomycetes bacteria produce diverse bioactive molecules that are useful as drug seeds. To improve their yield, researchers often optimize the fermentation medium. However, exactly how the extracellular chemicals present in the medium activate secondary metabolite gene clusters remains unresolved. BR-1, a β-carboline compound, was recently identified as a chemical signal that enhanced reveromycin A production in Streptomyces sp. SN-593. Here we show that BR-1 specifically bound to the transcriptional regulator protein RevU in the reveromycin A biosynthetic gene cluster, and enhanced RevU binding to its promoter. RevU belongs to the LuxR family regulator that is widely found in bacteria. Interestingly, BR-1 and its derivatives also enhanced the production of secondary metabolites in other Streptomyces species. Although LuxR-N-acyl homoserine lactone systems have been characterized in Gram-negative bacteria, we revealed LuxR-β-carboline system in Streptomyces sp. SN-593 for the production of secondary metabolites. This study might aid in understanding hidden chemical communication by β-carbolines.
Highlights
Microorganisms utilize a variety of communication systems that enable them to send and receive chemical signals to one another[1]
We did not observe metabolites, we found that cluster 10, encoding a type I polyketide synthase (PKS), was moderately upregulated after BR-1 treatment (Table S1). mRNA expression of most genes in cluster 18 (RM-A gene cluster) was significantly increased in the presence of BR-1, compared to untreated cells (Fig. 2)
We examined whether BR-1 treatment could recover the loss of RM production caused by disrupting the revU gene
Summary
Microorganisms utilize a variety of communication systems that enable them to send and receive chemical signals to one another[1]. FRI-510, SCB1 in Streptomyces coelicolor[11], and SRB1 in Streptomyces rochei[12] are known to promote morphological development and regulating secondary metabolism. Except for some ARCs, which inhibit fatty acid biosynthesis, the mechanisms of how extracellular chemical signals activate SM biosynthesis have not been clarified. This led us to speculate that extracellular chemical signals present in nature can enhance SM production. Based on a chemical biology approach, we identified that the target of β-carboline was a LuxR family transcriptional regulator in the RM gene cluster. Production of autoinducer and subsequent cell responses through LuxR regulators are well characterized in Gram-negative bacteria[29,30]. We discovered that the hidden chemical signal by β-carboline alkaloids through LuxR family regulator was linked with the production of RMs in Streptomyces sp.
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