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Enhancing the production of amphotericin B by Strepyomyces nodosus in a 50-ton bioreactor based on comparative genomic analysis

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Abstract

Amphotericin, as an important macrolide antibiotic, is synthesized by Streptomyces nodosus. A high-yield S. nodosus ZJB2016050 was obtained by mutagenesis in our lab with the advantages of high yield, short fermentation cycle and few by-products, which was more suitable for industrial production. The fermentation differences in 50-tons bioreactor between S. nodosus ATCC14899 and S. nodosus ZJB2016050 were compared. The amphotericin B (AmB) yield of S. nodosus ZJB2016050 was 9.73 mg/g at 96 h, which was 30% higher than that of S. nodosus ATCC14899. The by-product amphotericin A (AmA) production of S. nodosus ZJB2016050 was 78% lower than that of S. nodosus ATCC14899. By performing whole-genome sequencing of S. nodosus ZJB2016050 and comparative genome analysis with the wild-type S. nodosus ATCC14899, it was found that the two strains have high synteny, but each has a special gene fragment. The genes functions of fragment were identified in the amino acid transport and metabolism, carbohydrate metabolism and lipid transport and metabolism. The gene functions of SNP (single nucleotide polymorphism) genes were identified in amino acid transport and metabolism, carbohydrate metabolism, coenzyme metabolism and secondary metabolites biosynthesis. The difference in signal-regulation and transcription may be the main reason for the differences between these two strains. Three GntR family egulatory factors of S. nodosus ATCC14899 may reduce the synthesis of amphotericin. Based on the analysis of comparative genomes, the effects of corn oil in S. nodosus ATCC14899 and S. nodosus ZJB2016050 were also compared. The results showed that corn oil can promote the fermentation of S. nodosus ZJB2016050. The S. nodosus ZJB2016050 may degrade fatty acids faster, and the degraded acyl-coenzyme can be used to synthesize amphotericin.

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Acknowledgements

This research was funded by the Project from Department of Education of Zhejiang Province (No. Y201636181) and Zhejiang Provincial Public Welfare Technology Application Research Projects (No. LGF19B060004).

Access number and unlabeled genes sequence: The genome sequencing data has been upload to NCBI (The National Center for Biotechnology Information) database (https://www.ncbi.nlm.nih.gov/). CP071465 was sequence access number. The sequence of S. nodosus ZJB2016050 unique genes were listed in supplementary materials. The MiXs table was listed in Table S3.

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Authors and Affiliations

  1. The National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals, Zhejiang University of Technology, Hangzhou, 310014, People’s Republic of China

    Kai Huang, Bo Zhang, Yu Chen, Zhe-Ming Wu, Zhi-Qiang Liu & Yu-Guo Zheng

  2. Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, People’s Republic of China

    Kai Huang, Bo Zhang, Yu Chen, Zhe-Ming Wu, Zhi-Qiang Liu & Yu-Guo Zheng

  3. Zhejiang Tiantai Pharmaceutical Co., Ltd., Taizhou, Zhejiang, 317200, People’s Republic of China

    Zhe-Ming Wu

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  1. Kai Huang
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  2. Bo Zhang
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  4. Zhe-Ming Wu
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Contributions

KH and BZ conceived and designed research. KH and YC conducted experiments. Prof ZQL and Prof YGZ contributed reagents or analytical tools. KH and ZMW analyzed data. KH wrote and modified the manuscript.

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Correspondence to Zhi-Qiang Liu.

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

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Huang, K., Zhang, B., Chen, Y. et al. Enhancing the production of amphotericin B by Strepyomyces nodosus in a 50-ton bioreactor based on comparative genomic analysis. 3 Biotech 11, 299 (2021). https://doi.org/10.1007/s13205-021-02844-2

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  • DOI: https://doi.org/10.1007/s13205-021-02844-2

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