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Effects of methyl oleate and microparticle-enhanced cultivation on echinocandin B fermentation titer

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Abstract

Echinocandin B (ECB) is a key precursor of antifungal agent Anidulafungin, which has demonstrated clinical efficacy in patients with invasive candidiasis. In this study, the effects of microparticle-enhanced cultivation and methyl oleate on echinocandin B fermentation titer were investigated. The results showed that the titer was significantly influenced by the morphological type of mycelium, and mycelium pellet was beneficial to improve the titer of this secondary metabolism. First, different carbon sources were chosen for the fermentation, and methyl oleate achieved the highest echinocandin B titer of 2133 ± 50 mg/L, which was two times higher than that of the mannitol. The study further investigated the metabolic process of the fermentation, and the results showed that L-threonine concentration inside the cell could reach 275 mg/L at 168 h with methyl oleate, about 2.5 times higher than that of the mannitol. Therefore, L-threonine may be a key precursor of echinocandin B. In the end, a new method of adding microparticles for improving the mycelial morphology was used, and the addition of talcum powder (20 g/L, diameter of 45 µm) could make the maximum titer of echinocandin B reach 3148 ± 100 mg/L.

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References

  1. Fritz B, Jakob N, Nyfeler R, Hansjörg T, Walter V (1974) Echinocandin B, ein neuartiges polypeptid-antibioticum aus Aspergillus nidulans var. echinulatus: isolierung und bausteine. Helv Chem 57(8):2459–2477

    Article  Google Scholar 

  2. Kurtz MB, Heath IB, Marrinan J, Dreikorn S, Onishi J, Douglas C (1994) Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-β-D-glucan synthase. Antimicrob Agents Chemother 38:1480–1489

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Morris MI, Villmann M (2006) Echinocandins in the management of invasive fungal infections, part 2. Am J Health-syst 63(18):1693–1703

    CAS  Google Scholar 

  4. Robbins N, Wright GD, Cowen LE (2016) Antifungal drugs: the current armamentarium and development of new agents. Microbiol Spectr 4(5):903–904

    Google Scholar 

  5. Denning DW (2002) Echinocandins: a new class of antifungal. J Antimicrob Chemother 49(6):889–891

    Article  PubMed  CAS  Google Scholar 

  6. Cappelletty D, Eiselstein-Mckitrick K (2007) The echinocandins. Pharmacother J Hum Pharmacol Durg Ther 27(3):369–388

    Article  CAS  Google Scholar 

  7. Carter NJ, Keating GM (2009) Micafungin: a review of its use in the prophylaxis and treatment of invasive candida infections in pediatric patients. Pediatr Drugs 11(4):271–291

    Article  Google Scholar 

  8. Groll AH, Tragiannidis A (2009) Recent advances in antifungal prevention and treatment. Semin Hematol 46(3):212–229

    Article  PubMed  CAS  Google Scholar 

  9. Zou SP, Zhong W, Xia CJ, Gu YN, Niu K, Zheng YG (2015) Mutagenesis breeding of high echinocandin B producing strain and further titer improvement with culture medium optimization. Bioprocess Biosyst Eng 38(10):1845–1854

    Article  PubMed  CAS  Google Scholar 

  10. Hu ZC, Peng LY, Zheng YG (2016) Enhancement of echinocandin B production by a UV- and microwave-induced mutant of Aspergillus nidulans with precursor and biotin supplying strategy. Appl Biochem Biotechnol 179(7):1213–1226

    Article  PubMed  CAS  Google Scholar 

  11. Antecka A, Bizukojc M, Ledakowicz S (2016) Modern morphological engineering techniques for improving productivity of filamentous fungi in submerged cultures. World J Microbiol Biotechnol 32(12):193–202

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Lu F, Ping K, Wen L, Zhao W, Wang Z, Chu J (2015) Enhancing gluconic acid production by controlling the morphology of Aspergillus niger in submerged fermentation. Process Biochem 50(9):1342–1348

    Article  CAS  Google Scholar 

  13. Hama S, Onodera K, Yoshida A, Noda H, Kondo A (2015) Improved production of phospholipase A1 by recombinant Aspergillus oryzae through immobilization to control the fungal morphology under nutrient-limited conditions. Biochem Eng J 96:1–6

    Article  CAS  Google Scholar 

  14. Yang J, Jiao RH, Yao LY, Han WB, Lu YH, Tan RX (2016) Control of fungal morphology for improved production of a novel antimicrobial alkaloid by marine-derived fungus Curvularia sp. IFB-Z10 under submerged fermentation. Process Biochem 51(2):185–194

    Article  CAS  Google Scholar 

  15. Barriosgonzalez J, Miranda RU (2010) Biotechnological production and applications of statins. Appl Microbiol Biotechnol 85(4):869–883

    Article  CAS  Google Scholar 

  16. Bizukojc M, Ledakowicz S (2010) The morphological and physiological evolution of Aspergillus terreus mycelium in the submerged culture and its relation to the formation of secondary metabolites. World J Microbiol Biotechnol 26(1):41–54

    Article  CAS  Google Scholar 

  17. Papagianni M (2004) Fungal morphology and metabolite production in submerged mycelial processes. Biotechnol Adv 22(3):189–259

    Article  PubMed  CAS  Google Scholar 

  18. Mahesh N, Balakumar S, Indumathi P, Ayyadurai A, Viverk R (2012) Production and optimization of Mevastatin using Penicillium citrinum NCIM 768. J Microb Biochem Technol 4(1):1–4

    Article  CAS  Google Scholar 

  19. Rateb ME, Ebel R (2011) Secondary metabolites of fungi from marine habitats. Nat Prod Rep 28(2):290–344

    Article  PubMed  CAS  Google Scholar 

  20. Mcintyre M, Muller C, Dynesen J, Nielsen J (2001) Metabolic engineering of the morphology of Aspergillus metabolic engineering. Adv Biochem Eng Biotechnol 68(4):1827–1836

    Google Scholar 

  21. Driouch H, Sommer B, Wittmann C (2010) Morphology engineering of Aspergillus niger for improved enzyme production. Biotechnol Bioeng 105(6):1058–1068

    PubMed  CAS  Google Scholar 

  22. Krull R, Wucherpfennig T, Esfandabadi ME, Walisko R, Melzer G, Hempel DC (2013) Characterization and control of fungal morphology for improved production performance in biotechnology. J Biotechnol 163(2):112–123

    Article  PubMed  CAS  Google Scholar 

  23. Zou SP, Liu M, Wang QL, Xiong Y, Niu K, Zheng YG (2015) Preparative separation of echinocandin B from Aspergillus nidulans broth using macroporous resin adsorption chromatography. J Chromatogr B 978:111–117

    Article  CAS  Google Scholar 

  24. Hounoum BM, Blasco H, Emond P, Mavel S (2016) Liquid chromatography-high-resolution mass spectrometry-based cell metabolomics: experimental design, recommendations, and applications. TrAC Trends Anal Chem 75:118–128

    Article  CAS  Google Scholar 

  25. Fu YQ, Li S, Chen Y, Xu Q, Huang H, Sheng XY (2010) Enhancement of fumaric acid production by Rhizopus oryzae using a two-stage dissolved oxygen control strategy. Appl Biochem Biotechnol 162(4):1031–1038

    Article  PubMed  CAS  Google Scholar 

  26. Emri T, Majoros L, Toth V, Pocsi I (2013) Echinocandins: production and applications. Appl Microbiol Biotechnol 97:3267–3284

    Article  PubMed  CAS  Google Scholar 

  27. Cacho RA, Jiang W, Chooi YH, Walsh CT, Tang Y (2012) Identification and characterization of the echinocandin B biosynthetic gene cluster from Emericella rugulosa NRRL 11440. J Am Chem Soc 134:16781–16790

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Chen L, Liu X, An Z, Yue Q, Zhang X, Xiang M (2013) Genomics-driven discovery of pneumocandin biosynthetic gene cluster in the fungus Glarea lozoyensis. BMC Genom 14(1):339–357

    Article  CAS  Google Scholar 

  29. Mouslim J, David L, Pétel G (1993) Effect of exogeneous methyl oleate on the time course of some parameters of Streptomyces hygroscopicus NRRL B-1865 culture. Appl Microbiol Biotechnol 39:585–588

    Article  CAS  Google Scholar 

  30. Kaup BA, Ehrich K, Pescheck M, Schrader J (2008) Microparticle-enhanced cultivation of filamentous microorganisms: increased chloroperoxidase formation by Caldariomyces fumago as an example. Biotechnol Bioeng 99(3):491–498

    Article  PubMed  CAS  Google Scholar 

  31. Driouch H, Roth A, Dersch P, Wittmann C (2011) Filamentous fungi in good shape: microparticles for tailor-made fungal morphology and enhanced enzyme production. Bioeng Bugs 2(2):100–104

    Article  PubMed  Google Scholar 

  32. Niu K, Mao J, Zheng Y (2015) Effect of microparticle on fermentation process of filamentous microorganisms—a review. Acta Microbiol Sin 55(3):258–263

    CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the financial supports of the National Key Research and Development Project of China (2018YFA0901400).

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Authors and Affiliations

  1. The National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals, Zhejiang University of Technology, Hangzhou, 310014, People’s Republic of China

    Kun Niu, Xu-Ping Wu, Xiao-Long Hu, Shu-Ping Zou, Zhong-Ce Hu, Zhi-Qiang Liu & Yu-Guo Zheng

  2. Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, People’s Republic of China

    Kun Niu, Xu-Ping Wu, Xiao-Long Hu, Shu-Ping Zou, Zhong-Ce Hu, Zhi-Qiang Liu & Yu-Guo Zheng

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  1. Kun Niu
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Correspondence to Zhi-Qiang Liu.

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Niu, K., Wu, XP., Hu, XL. et al. Effects of methyl oleate and microparticle-enhanced cultivation on echinocandin B fermentation titer. Bioprocess Biosyst Eng 43, 2009–2015 (2020). https://doi.org/10.1007/s00449-020-02389-3

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  • DOI: https://doi.org/10.1007/s00449-020-02389-3

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