Applied Microbiology and Biotechnology

, Volume 102, Issue 24, pp 10729–10742 | Cite as

Novel osmotic stress control strategy for improved pneumocandin B0 production in Glarea lozoyensis combined with a mechanistic analysis at the transcriptome level

  • Ping Song
  • Baoqi Huang
  • Sen Zhang
  • Ke Zhang
  • Kai Yuan
  • Xiaojun Ji
  • Lujing Ren
  • Jianping Wen
  • He HuangEmail author
Applied microbial and cell physiology


Pneumocandin B0, the precursor of the antifungal drug caspofungin, is a secondary metabolite of the fungus Glarea lozoyensis. In this study, we investigated the effects of mannitol as the sole carbon source on pneumocandin B0 production by G. lozoyensis. The osmotic pressure is more important in enhancing pneumocandin B0 production than is the substrate concentration. Based on the kinetic analysis, an osmotic stress control fed-batch strategy was developed. This strategy led to a maximum pneumocandin B0 concentration of 2711 mg/L with a productivity of 9.05 mg/L/h, representing 34.67 and 6.47% improvements, respectively, over the best result achieved by the one-stage fermentation. Furthermore, G. lozoyensis accumulated glutamate and proline as compatible solutes to resist osmotic stress, and these amino acids also provided the precursors for the enhanced pneumocandin B0 production. Osmotic stress also activated ROS (reactive oxygen species)-dependent signal transduction by upregulating the levels of related genes and increasing intracellular ROS levels by 20%. We also provided a possible mechanism for pneumocandin B0 accumulation based on signal transduction. These findings will improve our understanding of the regulatory mechanisms of pneumocandin B0 biosynthesis and may be applied to improve secondary metabolite production.


Osmotic stress Fed-batch Secondary metabolite Fungi Transcriptome analysis 



This work was supported by the Natural Science Fund for Colleges and Universities in Jiangsu Province (No. 17KJB530006), the Natural Science Foundation of Jiangsu Province (BK20161048), the National Science Foundation of China (No. 21776136), the Program for Innovative Research Teams in Universities of Jiangsu Province (2015), the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (No. PPZY2015B155), and the Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture (No. XTE1854).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

253_2018_9440_MOESM1_ESM.pdf (686 kb)
ESM 1 (PDF 686newnbsp;kb)


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Copyright information

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

Authors and Affiliations

  1. 1.SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
  2. 2.Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture, College of Biotechnology and Pharmaceutical EngineeringNanjing Tech UniversityNanjingChina
  3. 3.Jiangsu Collaboration Innovation Center of Chinese Medical Resources Industrialization, College of PharmacyNanjing University of Chinese MedicineNanjingChina
  4. 4.School of Pharmaceutical SciencesNanjing Tech UniversityNanjingChina

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