Comparative metabolomics analysis of amphotericin B high-yield mechanism for metabolic engineering

Microbial Cell Factories

Yu Chen¹  Xue Cai¹  Yu-Guo Zheng¹  Zhi-Qiang Liu¹  Bo Zhang¹  Kai Huang¹  Sheng-Xian Jiang¹ 

[1] Department, Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 310014, Hangzhou, People’s Republic of China;Engineering Research Center of Bioconversion and Bio-Purification, Ministry of Education, Zhejiang University of Technology, 310014, Hangzhou, People’s Republic of China;

关键词: Amphotericin B;    Streptomyces nodosus;    Comparative metabolomics analysis;    Rational guidance;    Gene overexpression;   

DOI  :  10.1186/s12934-021-01552-z

来源: Springer

【 摘 要 】

BackgroundThe polyene macrocyclic compound amphotericin B (AmB) is an important antifungal antibiotic for the clinical treatment of invasive fungal infections. To rationally guide the improvement of AmB production in the main producing strain Streptomyces nodosus, comparative metabolomics analysis was performed to investigate the intracellular metabolic changes in wild-type S. nodosus ZJB20140315 with low-yield AmB production and mutant S. nodosus ZJB2016050 with high-yield AmB production, the latter of which reached industrial criteria on a pilot scale.ResultsTo investigate the relationship of intracellular metabolites, 7758 metabolites were identified in mutant S. nodosus and wildtype S. nodosus via LC–MS. Through analysis of metabolism, the level of 26 key metabolites that involved in carbon metabolism, fatty acids metabolism, amino acids metabolism, purine metabolism, folate biosynthesis and one carbon pool by folate were much higher in mutant S. nodosus. The enrichment of relevant metabolic pathways by gene overexpression strategy confirmed that one carbon pool by folate was the key metabolic pathway. Meanwhile, a recombinant strain with gene metH (methionine synthase) overexpressed showed 5.03 g/L AmB production within 120 h fermentation, which is 26.4% higher than that of the mutant strain.ConclusionsThese results demonstrated that comparative metabolomics analysis was an effective approach for the improvement of AmB production and could be applied for other industrially or clinically important compounds as well.

【 授权许可】

CC BY