Novel osmotic stress control strategy for improved pneumocandin B 0 production in Glarea lozoyensis combined with a mechanistic analysis at the transcriptome level

• Published in: Applied microbiology and biotechnology 2018-12, Vol.102 (24), p.10729
• Main Authors: Song, Ping, Huang, Baoqi, Zhang, Sen, Zhang, Ke, Yuan, Kai, Ji, Xiaojun, Ren, Lujing, Wen, Jianping, Huang, He
• Format: Article
• Language: English
• Subjects: Antioxidants - metabolism; Ascomycota - drug effects; Ascomycota - genetics; Ascomycota - growth & development; Ascomycota - metabolism; Carbon - metabolism; Echinocandins - metabolism; Enzymes - genetics; Enzymes - metabolism; Fermentation; Fungal Proteins - genetics; Fungal Proteins - metabolism; Gene Expression Profiling; Gene Expression Regulation, Fungal; Mannitol - metabolism; Mannitol - pharmacology; Osmotic Pressure - physiology; Signal Transduction - genetics
• ISSN: 1432-0614
• DOI: 10.1007/s00253-018-9440-4

Pneumocandin B , 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 B production by G. lozoyensis. The osmotic pressure is more important in enhancing pneumocandin B 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 B 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 B 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 B accumulation based on signal transduction. These findings will improve our understanding of the regulatory mechanisms of pneumocandin B biosynthesis and may be applied to improve secondary metabolite production.