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Enhancement of antibiotic productions by engineered nitrate utilization in actinomycetes

  • Applied genetics and molecular biotechnology
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Abstract

Nitrate is necessary for primary and secondary metabolism of actinomycetes and stimulates the production of a few antibiotics, such as lincomycin and rifamycin. However, the mechanism of this nitrate-stimulating effect was not fully understood. Two putative ABC-type nitrate transporters were identified in Streptomyces lincolnensis NRRL2936 and verified to be involved in lincomycin biosynthesis. With nitrate supplementation, the transcription of nitrogen assimilation genes, nitrate-specific ABC1 transporter genes, and lincomycin exporter gene lmrA was found to be enhanced and positively regulated by the global regulator GlnR, whose expression was also improved. Moreover, heterologous expression of ABC2 transporter genes in Streptomyces coelicolor M145 resulted in an increased actinorhodin production. Further incorporation of a nitrite-specific transporter gene nirC, as in nirC-ABC2 cassette, led to an even higher actinorhodin production. Similarly, the titers of salinomycin, ansamitocin, lincomycin, and geldanamycin were increased with the integration of this cassette to Streptomyces albus BK3-25, Actinosynnema pretiosum ATCC31280, S. lincolnensis LC-G, and Streptomyces hygroscopicus XM201, respectively. Our work expanded the nitrate-stimulating effect to many antibiotic producers by utilizing the nirC-ABC2 cassette for enhanced nitrate utilization, which could become a general tool for titer increase of antibiotics in actinomycetes.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 31401056, 31300081, 21661140002, 31470157, 31400030), the Ministry of Science and Technology of China (No. 2012CB721005), and the Open Funding Project of State Key Laboratory of Microbial Metabolism.

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  1. State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China

    Sitong Meng, Lei Wang & Linquan Bai

  2. Institute of Health Sciences, School of Life Sciences, Anhui University, Hefei, 230601, China

    Hang Wu & Buchang Zhang

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  1. Sitong Meng
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  5. Linquan Bai
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Correspondence to Linquan Bai.

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Meng, S., Wu, H., Wang, L. et al. Enhancement of antibiotic productions by engineered nitrate utilization in actinomycetes. Appl Microbiol Biotechnol 101, 5341–5352 (2017). https://doi.org/10.1007/s00253-017-8292-7

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