Abstract
The aim of the present study was to optimize the feeding proportion of glucose and propanol for erythromycin biosynthesis by real-time monitoring and exploring its limited ratio by the on-line multi-frequency permittivity measurement. It was found that the capacitance values were sensitive to the variation of biomass concentration and microbial morphology as well as the true state of cell growth. It was most favorable to both cell growth and secondary metabolism to keep the ratio of glucose to propanol at 4.3 (g/g). The specific growth rate calculated by the capacitance measurement correctly and accurately reflected the cell physiological state. An appropriate feed rate of propanol was crucial for cell growth and secondary metabolism, as well as to improve the quality of erythromycin-A. In addition, the erythromycin production titer (10,950 U/mL) was further enhanced by 4 % when the propanol feed was regulated by step-down strategy based on both OUR (oxygen uptake rate) and the on-line monitoring capacitance.
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Bao K, Zhang WG, Cheng MS (2009) Recent developments in erythromycin derivatives with new bioactivities. J Shenyang Pharm Univ 26(1):74–79
Mironov VA, Sergienko OV, Nastasyak IN, Danilenko VN (2004) Biogenesis and regulation of biosynthesis of erythromycins in Saccharopolysplra erythraea. Appl Biochem Microbiol 6:611–624
Sun Y, Zhou RQ, Wu Q (2005) Biochemistry and genetics of erythromycin biosynthesis. J Microbiol 25(2):45
Andrew R, Reeves Igor A, Brikun William H (2006) Effects of methylmalonyl-CoA mutase gene knockouts on erythromycin production in carbohydrate-based and oil-based fermentations of Saccharopolyspora erythraea. J Ind Microbiol Biotechnol 33(7):600–609
Chen Y, Deng W, Wu JQ (2008) Genetic modulation of the over expression of tailoring genes eryK and eryG leading to the improvement of erythromycin A purity and production in Saccharopolyspora erythrae. Appl Environ Microbiol Ferment 74(6):1820–1828
Shen ZB, Chen GH, Chen CH (2006) Study on effect of soybean oil on fermentation of erythromycin and its mechanism. Chin J Antibiot 31(11):657–660
Elmahdi I, Baganz F, Dixon K, Harropb T, Sµgden D, Lye GJ (2003) pH control in microwell fermentations of S. erythraea CA340 influence on biomass growth kinetics and erythromycin biosynthesis. Biochem Eng J 16:299–310
Chen Y, Huang MZ, Wang ZJ, Chu J et al (2013) Controlling the feed rate of glucose and propanol for the enhancement of erythromycin production and exploration of propanol metabolism fate by quantitative metabolic flux analysis. Bioprocess Biosyst Eng 36(10):1445–1453
Staunton J, Wilkinson B (1997) Biosynthesis of erythromycin and rapamycin. Chem Rev 7:2611–2630
Chan YA, Podevels AM, Kevany BM, Thomas GM (2009) Biosynthesis of polyketide synthase extender units. Nat Prod Rep 1:90–114
Bojanowsa KR, Ruczaj Z, Korszynka DS, Rafalski A (1973) Limiting reaction in activation of acyl units in biosynthesis of macrolide antibiotics. Antimicrob Agents CH 2:162–167
Zhang YP, Liu M, Du CY, Shen JY, Cao ZA (2006) Effect of by-products on cell growth and biosynthesis of 1,3-propanediol by Klebsiella pneumoniae. Chin J Process Eng 6(5):804–808
Carvell JP, Dowd JE (2006) On-line measurements and control of viable cell density in cell culture manufacturing processes using radio-frequency impedance. Cyto Technol 50:35–48
Arnold SA, Gaenakoo R, Harvey LM et al (2002) Use of at-line and in situ near-infrared spectroscope to monitor biomass in an industrial fed-batch Escherichia coli process. Biotechnol Bioeng 80:405–413
Soly A, Lecina M, Gamez X (2005) On-line monitoring of yeast cell growth by impedance spectroscopy. J Biotechnol 118:398–405
Ferreira AP, Vieira LM, Cardoso JP et al (2005) Evaluation of a new annular capacitance probe for biomass monitoring in industrial pilot-scale fermentations. J Biotechnol 116:403–409
Wang YJ, Fan Y (2000) Studies of on-line and in situ measuring method for biomass concentration. Prog Biochem Biophys 27(4):387–390
Kiviharju K, Salonen K, Moilanen U, Eerikainen T (2008) Biomass measurement online: the performance of in situ measurements and software sensors. Ind Microbiol Biotechnol 35:657–665
Patel P, Bhat A, Markx G (2008) A comparative study of cell death using electrical capacitance measurements and dielectrophoresis. Enzyme Microb Technol 43:523–530
Bryant D, Morris S, Leemans D, Fish S, Taylor S, Carvell J, Todd R, Logan D, Lee M, Garcia N, Ellis A, Gallagher J (2011) Modelling real-time simultaneous saccharification and fermentation of lignocellulosic biomass and organic acid accumulation using dielectric spectroscopy. Bioresour Technol 102:9675–9682
Neves AA, Pereira DA, Vieira LM et al (2001) Real time monitoring biomass concentration in Streptomyces clavuligerus cultivations with industrial media using a capacitance probe. J Biotechnol 84:45–52
Cannizaaro C, Gugerli R, Marison I et al (2003) On-line biomass monitoring of CHO perfusion culture with scanning dielectric spectroscopy. Biotechnol Bioeng 84:597–610
Liu YW, Huang MZ, Zhou Y et al (2010) Study on online capacitance viable-cell mass monitoring in citric acid fermentation by Aspergillus niger in complex medium with corn dregs. Food Ferment Ind 36(12):1–5
Maskow T, Röllich A, Fetzer I, Ackermann JU, Harms H (2008) On-line monitoring of lipid accumulation in yeast using impedance spectroscopy. J Biotechnol 135:64–70
Zou X, Hang HF, Chu J, Zhuang YP, Zhang SL (2009) Oxygen uptake rate optimization with nitrogen regulation for erythromycin production and scale-up from 50 L to 372 m3 scale. Bioresour Technol 3:1406–1412
Liu F, Jin YR (1996) Determination of amino-nitrogen in chong cao Beijing oral liquid by formaldehyde titration. Acta Acad Med Zhejiang 7(1):15–18
Fan DD, Chen B, Shang LA, Shen LX, Li BZ et al (1999) The improvement of fermentation technical parameters for the erythrus-mycin formation. Chin J Biotechnol 15(1):104–108
Qi XC, Chen CF, Qian JC, Chu J et al (2009) Determination of the erythromycin components in fermentation broth by HPLC. Food Ferment Ind 7:151–155
Licona-Cassani C, Marcellin E, Quek LE, Jacob S, Nielsen LK (2012) Reconstruction of the Saccharopolyspora erythraea genome-scale model and its use for enhancing erythromycin production. Antonie Van Leeuwenhoek Int J Gen Mol Microbiol 102(3):493–502
Steven MM, Michael EB (1996) Effect of hyphal micromorphology on bioreactor performance of antibiotic-producing Saccharopolyspora erythraea cultures. Microbiology 142:1783–1788
Liu Y, Ye RF, Zheng L et al (2005) Effects of propanol, Cu2+ and niacinamide on biosythesis of erythromycin. J East China Univ Sci Technol 31(6):808–811
Acknowledgments
This work was financially supported by a grant from National Natural Science Foundation of China(No. 21276081), the Major State Basic Research Development Program of China (973 Program, No. 2012CB721006), the National Scientific and Technological Major Special Project (Significant Creation of New drugs, No. 2011ZX09203-001-03), and Research Fund for the Doctoral Program of Higher Education of China (No. 20110074110015).
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Guo, Q., Chu, J., Zhuang, Y. et al. Controlling the feed rate of propanol to optimize erythromycin fermentation by on-line capacitance and oxygen uptake rate measurement. Bioprocess Biosyst Eng 39, 255–265 (2016). https://doi.org/10.1007/s00449-015-1509-1
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DOI: https://doi.org/10.1007/s00449-015-1509-1