Abstract
BackgroundOmics approaches have significantly increased our understanding of biological systems. However, they have had limited success in explaining the dramatically increased productivity of commercially important natural products by industrial high-producing strains, such as the erythromycin-producing actinomycete Saccharopolyspora erythraea. Further yield increase is of great importance but requires a better understanding of the underlying physiological processes.ResultsTo reveal the mechanisms related to erythromycin yield increase, we have undertaken an integrated study of the genomic, transcriptomic, and proteomic differences between the wild type strain NRRL2338 (WT) and the industrial high-producing strain ABE1441 (HP) of S. erythraea at multiple time points of a simulated industrial bioprocess. 165 observed mutations lead to differences in gene expression profiles and protein abundance between the two strains, which were most prominent in the initial stages of erythromycin production. Enzymes involved in erythromycin biosynthesis, metabolism of branched chain amino acids and proteolysis were most strongly upregulated in the HP strain. Interestingly, genes related to TCA cycle and DNA-repair were downregulated. Additionally, comprehensive data analysis uncovered significant correlations in expression profiles of the erythromycin-biosynthetic genes, other biosynthetic gene clusters and previously unidentified putative regulatory genes. Based on this information, we demonstrated that overexpression of several genes involved in amino acid metabolism can contribute to increased yield of erythromycin, confirming the validity of our systems biology approach.ConclusionsOur comprehensive omics approach, carried out in industrially relevant conditions, enabled the identification of key pathways affecting erythromycin yield and suggests strategies for rapid increase in the production of secondary metabolites in industrial environment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0496-5) contains supplementary material, which is available to authorized users.
Highlights
Omics approaches have significantly increased our understanding of biological systems
Genome of the high‐producing S. erythraea strain ABE1441 The order-of-magnitude increase in erythromycin yield, displayed in industrial cultivation conditions by the high-producing strain ABE1441 (HP) strain [22] compared to wild type strain NRRL2338 (WT), as well as all differences in the metabolism between the two strains stem from genomic mutations
Generation sequencing of the HP strain revealed 165 genuine mutations compared to WT, affecting 147 genes
Summary
Omics approaches have significantly increased our understanding of biological systems. Soil-dwelling actinomycete bacteria are prolific producers of diverse biologically active secondary metabolites, which have found widespread use in human and veterinary medicine, as well as in agriculture [7]. These substances include antibiotics, antifungal, anti-cancer, immunosuppressive, insecticide, and other classes of bioactive substances of immense value for human health and the global economy. In natural environments these compounds are produced by bacterial cells in very small amounts as non-essential secondary metabolites. They are full of uncharacterized mutations that disrupt their normal developmental cycle, make them more sensitive to environmental conditions, and hinder further yield optimization
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