BACKGROUND Amphotericin B (AmB) is widely used against fungal infection and produced mainly by Streptomyces nodosus. Various intracellular metabolites of S. nodosus were identified during AmB fermentation, and the key compounds that related to the cell growth and biosynthesis of AmB were analyzed by principal component analysis (PCA) and partial least squares (PLS). RESULTS Rational design that based on the results of metabolomics was employed to improve the AmB productivity of Streptomyces nodosus, including the overexpression of genes involved in oxygen-taking, precursor-acquiring and product-exporting. The AmB yield of modified strain S. nodosus VMR4A was 6.58 g/L, which was increased significantly in comparison with that of strain S. nodosus ZJB2016050 (5.16 g/L). This was the highest yield of AmB reported so far, and meanwhile, the amount of by-product amphotericin A (AmA) was decreased by 45%. Moreover, the fermentation time of strain S. nodosus VMR4A was shortened by 24 h compared with that of strain. The results indicated that strain S. nodosus VMR4A was an excellent candidate for the industrial production of AmB because of its high production yield, low by-product content and the fast cell growth. CONCLUSIONS This study would lay the foundation for improving the AmB productivity through metabolomics analysis and overexpression of key enzymes.

中文翻译：

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结节链霉菌中两性霉素B的生物合成：通过基于LC-MS / MS的代谢组学对代谢进行定量分析，以进行合理设计。

背景技术两性霉素B（AmB）被广泛用于抵抗真菌感染，主要由结节链霉菌产生。在AmB发酵过程中鉴定了No.us的各种细胞内代谢产物，并通过主成分分析（PCA）和偏最小二乘（PLS）分析了与AmB的细胞生长和生物合成有关的关键化合物。结果采用基于代谢组学结果的合理设计，可提高结节链霉菌的AmB生产率，包括与吸氧，获取前体和输出产品有关的基因的过表达。改良的S. nodosus菌株VMR4A的AmB产量为6.58 g / L，与No. S. nodosus ZJB2016050的菌株（5.16 g / L）相比明显增加。这是迄今为止报道的AmB的最高产量，与此同时，副产物两性霉素A（AmA）的含量降低了45％。此外，与菌株相比，菌株No.sus VMR4A的发酵时间缩短了24小时。结果表明，由于其高产率，低副产物含量和快速的细胞生长，菌株No.sus VMR4A是AmB的工业生产的极好的候选者。结论本研究将通过代谢组学分析和关键酶的过表达为提高AmB生产率奠定基础。低的副产物含量和快速的细胞生长。结论本研究将通过代谢组学分析和关键酶的过表达为提高AmB生产率奠定基础。低的副产物含量和快速的细胞生长。结论本研究将通过代谢组学分析和关键酶的过表达为提高AmB生产率奠定基础。