Generation of new compounds through unbalanced transcription of landomycin A cluster
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The biosynthetically well-studied landomycin A cluster has been used to demonstrate the unbalancing of gene transcription as an efficient method for the generation of new compounds. Landomycin A structural genes were decoupled from the native regulators LanI and LanK and placed under the control of a single synthetic promoter and expressed in a heterologous host Streptomyces albus J1074. In contrast to their native quantitative and temporal regulation, these genes were transcribed as a single polycistronic mRNA leading to the production of four novel and two known compounds. No glycosylated landomycins were detected though the entire biosynthetic cluster was transcribed, showing the crucial role of the balanced gene expression for the production of landomycin A. Two new compounds, fridamycin F and G, isolated in this study were shown to originate from the interplay between the expressed biosynthetic pathway and metabolic network of the heterologous host. Structure activity studies of the isolated compounds as well as results of transcriptome sequencing are discussed in this article.
KeywordsLandomycin A Angucyclines Transcriptional unbalancing Natural product discovery Synthetic promoters Streptomyces albus
Authors are very grateful to Dr. Jennifer Herrmann and Prof. Rolf Müller from Helmholtz Institute of Pharmaceutical Sciences Saarland (Saarbrücken, Germany) for the help with performing MIC assay.
Compliance with ethical standards
This article does not contain any studies with human participants or animals performed by any of the authors.
This work was supported by the European Commission under the 7th Framework Programme through the “Collaborative Project” action, “STREPSYNTH” grant no. 613877 and through the ERC starting grant EXPLOGEN No. 281623 to AL.
Conflict of interest
The authors declare that they have no conflict of interest.
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