Bioprocess and Biosystems Engineering

, Volume 41, Issue 10, pp 1529–1538 | Cite as

High-throughput optimization of the chemically defined synthetic medium for the production of erythromycin A

  • Ming Hong
  • Jianguo Liao
  • Ju ChuEmail author
Research Paper


Erythromycin A is an important antibiotic. A chemically defined synthetic medium for erythromycin production was systematically optimized in this study. A high-throughput method was employed to reduce the number of components and optimize the concentration of each component. After two round single composition deletion experiment, only 19 components were remained in the medium, and then the concentration of each component was optimized through PB experiment. The optimal medium from the PB experiment was further optimized according to the nitrogen and phosphate metabolic consumption in 5 L bioreactor. It was observed that among the 8 amino acids concluded in the media, 4 amino acids were first consumed, when they are almost depleted, the other 4 amino acids were initiated their consumption afterwards in 5 L bioreactor. The decrease of phosphate concentration would increase qglc and qery. However, when phosphate concentration was too low, the production of erythromycin was hindered. The positive correlation between intracellular metabolite pools and Yery/glc indicated that low phosphate concentration in the medium can promote cell metabolism especially secondary metabolism during the stationary phase; however, if it was too low (5 mmol/L), the cell metabolism and secondary metabolism would both slow down. The erythromycin titer in the optimized medium (medium V) reached 1380 mg/L, which was 17 times higher than the previously used synthetic medium in our lab. The optimized medium can facilitate the metabolomics study or metabolic flux analysis of the erythromycin fermentation process, which laid a solid foundation for further study of erythromycin fermentation process.


Chemically defined synthetic medium Erythromycin Saccharopolyspora erythraea Phosphate regulation Intracellular metabolite pools 



This work was financially supported by a grant from the Major State Basic Research Development Program of China (973 Program, no. 2012CB721006), National Natural Science Foundation of China (no. 21276081), partially supported by NWO-MoST Joint Program (2013DFG32630).

Compliance with ethical standards

Conflict of interest

There is no conflict of interest.


  1. 1.
    Oliynyk M, Samborskyy M, Lester JB, Mironenko T, Scott N, Dickens S, Haydock SF, Leadlay PF (2007) Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Nat Biotechnol 25:447–453CrossRefPubMedGoogle Scholar
  2. 2.
    Mironov VA, Sergienko OV, Nastasyak IN, Danilenko VN (2004) Biogenesis and regulation of biosynthesis of erythromycins in Saccharopolyspora erythraea. Appl Biochem Micro 40:531–541CrossRefGoogle Scholar
  3. 3.
    Li YY, Chang X, Yu WB, Li H, Ye ZQ, Yu H, Liu BH, Zhang Y, Zhang SL, Ye BC, Li YX (2013) Systems perspectives on erythromycin biosynthesis by comparative genomic and transcriptomic analyses of S. erythraea E3 and NRRL23338 strains. Bmc Genomics 14:523CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Wu J, Zhang Q, Deng W, Qian J, Zhang S, Liu W (2011) Toward improvement of erythromycin A production in an industrial Saccharopolyspora erythraea strain via facilitation of genetic manipulation with an artificial attB site for specific recombination. Appl Environ Microbiol 77:7508–7516CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Flores ME, Sánchez S (1985) Nitrogen regulation of erythromycin formation in Streptomyces erythreus. Fems Microbiol Lett 26:191–194CrossRefGoogle Scholar
  6. 6.
    Caffrey P, Bevitt DJ, Staunton J, Leadlay PF (1992) Identification of DEBS 1, DEBS 2 and DEBS 3, the multienzyme polypeptides of the erythromycin-producing polyketide synthase from Saccharopolyspora erythraea. Febs Lett 304:225–228CrossRefPubMedGoogle Scholar
  7. 7.
    Hsieh YJ, Kolattukudy PE (1994) Inhibition of erythromycin synthesis by disruption of malonyl-coenzyme A decarboxylase gene eryM in Saccharopolyspora erythraea. J Bacteriol 176:714–724CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bermúdez O, Padilla P, Huitrón C, Elenaflores M (1998) Influence of carbon and nitrogen source on synthesis of NADP+-isocitrate dehydrogenase, methylmalonyl-coenzyme A mutase, and methylmalonyl-coenzyme A decarboxylase in Saccharopolyspora erythraea CA340. Fems Microbiol Lett 164:77–82CrossRefGoogle Scholar
  9. 9.
    Zhang Q, Chen Y, Hong M, Gao Y, Chu J, Zhuang Y-P, Zhang S-l (2014) The dynamic regulation of nitrogen and phosphorus in the early phase of fermentation improves the erythromycin production by recombinant Saccharopolyspora erythraea strain. Biores Bioprocess 1:15CrossRefGoogle Scholar
  10. 10.
    Tan J, Chu J, Hao YY, Wang YH, Yao SC, Zhuang YP, Zhang SL (2013) A high-throughput screening strategy for accurate quantification of erythromycin. J Taiwan Inst Chem E 44:538–544CrossRefGoogle Scholar
  11. 11.
    Hong M, Mou H, Liu X, Huang M, Chu J (2017) (13)C-assisted metabolomics analysis reveals the positive correlation between specific erythromycin production rate and intracellular propionyl-CoA pool size in Saccharopolyspora erythraea. Bioproc Biosyst Eng 40:1–12CrossRefGoogle Scholar
  12. 12.
    Bibb MJ (2005) Regulation of secondary metabolism in streptomycetes. Curr Opin Microbiol 8:208–215CrossRefPubMedGoogle Scholar
  13. 13.
    Hong M, Huang M, Chu J, Zhuang Y, Zhang S (2016) Impacts of proline on the central metabolism of an industrial erythromycin-producing strain Saccharopolyspora erythraea via C labeling experiments. J Biotechnol 231:1–8CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.State Key Laboratory of Bioreactor EngineeringEast China University of Science and TechnologyShanghaiChina

Personalised recommendations