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

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Abstract

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.

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Funding

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).

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Authors and Affiliations

  1. SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, 92 Weijin Road, Tianjin, 300072, China

    Ping Song & Jianping Wen

  2. Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 South Puzhu Road, Nanjing, 211816, China

    Ping Song, Baoqi Huang, Ke Zhang, Kai Yuan, Xiaojun Ji & Lujing Ren

  3. Jiangsu Collaboration Innovation Center of Chinese Medical Resources Industrialization, College of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China

    Sen Zhang

  4. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, China

    He Huang

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  1. Ping Song
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  3. Sen Zhang
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Correspondence to He Huang.

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Song, P., Huang, B., Zhang, S. et al. Novel osmotic stress control strategy for improved pneumocandin B0 production in Glarea lozoyensis combined with a mechanistic analysis at the transcriptome level. Appl Microbiol Biotechnol 102, 10729–10742 (2018). https://doi.org/10.1007/s00253-018-9440-4

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