title: Integrated omics approaches provide strategies for rapid erythromycin yield increase in Saccharopolyspora erythraea.
abstract: BACKGROUND
  Omics 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.
  
  
  RESULTS
  To 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Acies Bio, d.o.o., Tehnološki park 21, SI-1000, Ljubljana, Slovenia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Karničar
authors.affiliation: Acies Bio, d.o.o., Tehnološki park 21, SI-1000, Ljubljana, Slovenia.|Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000, Ljubljana, Slovenia.
authors.forename: Igor
authors.initials: I
authors.lastname: Drobnak
authors.affiliation: Department of Biotechnology and Systems Biology, National Institute of Biology, Večna pot 111, SI-1000, Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Petek
authors.affiliation: Acies Bio, d.o.o., Tehnološki park 21, SI-1000, Ljubljana, Slovenia.
authors.forename: Vasilka
authors.initials: V
authors.lastname: Magdevska
authors.affiliation: Acies Bio, d.o.o., Tehnološki park 21, SI-1000, Ljubljana, Slovenia.
authors.forename: Jaka
authors.initials: J
authors.lastname: Horvat
authors.affiliation: Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, Jamova cesta 39, SI-1000, Ljubljana, Slovenia.|International Postgraduate School Jožef Stefan, Jamova cesta 39, SI-1000, Ljubljana, Slovenia.
authors.forename: Robert
authors.initials: R
authors.lastname: Vidmar
authors.affiliation: Department of Biotechnology and Systems Biology, National Institute of Biology, Večna pot 111, SI-1000, Ljubljana, Slovenia.
authors.forename: Špela
authors.initials: Š
authors.lastname: Baebler
authors.affiliation: Department of Biotechnology and Systems Biology, National Institute of Biology, Večna pot 111, SI-1000, Ljubljana, Slovenia.
authors.forename: Ana
authors.initials: A
authors.lastname: Rotter
authors.affiliation: Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, SI-1000, Ljubljana, Slovenia.
authors.forename: Polona
authors.initials: P
authors.lastname: Jamnik
authors.affiliation: Acies Bio, d.o.o., Tehnološki park 21, SI-1000, Ljubljana, Slovenia.
authors.forename: Štefan
authors.initials: Š
authors.lastname: Fujs
authors.affiliation: Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, Jamova cesta 39, SI-1000, Ljubljana, Slovenia.|Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva cesta 5, SI-1000, Ljubljana, Slovenia.|Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000, Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Turk
authors.affiliation: Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, Jamova cesta 39, SI-1000, Ljubljana, Slovenia.|Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000, Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Fonovič
authors.affiliation: Department of Biotechnology and Systems Biology, National Institute of Biology, Večna pot 111, SI-1000, Ljubljana, Slovenia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Gruden
authors.affiliation: Acies Bio, d.o.o., Tehnološki park 21, SI-1000, Ljubljana, Slovenia. gregor.kosec@aciesbio.com.
authors.forename: Gregor
authors.initials: G
authors.lastname: Kosec
authors.affiliation: Acies Bio, d.o.o., Tehnološki park 21, SI-1000, Ljubljana, Slovenia. hrvoje.petkovic@aciesbio.com.|Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, SI-1000, Ljubljana, Slovenia. hrvoje.petkovic@aciesbio.com.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Petković
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D001426:Bacterial Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D004917:Erythromycin / Q000096:biosynthesis* / Q000737:chemistry; D020869:Gene Expression Profiling; D005798:Genes, Bacterial; D023281:Genomics; D013058:Mass Spectrometry; D060847:Metabolic Engineering; D040901:Proteomics; D016930:Saccharopolyspora / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004917:Erythromycin
keywords: Erythromycin; Metabolic engineering; Polyketide; Proteomics; Saccharopolyspora erythraea; Substrate supply; Systems biology; Transcriptomics