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Mechanism of salinomycin overproduction in Streptomyces albus as revealed by comparative functional genomics

  • Applied genetics and molecular biotechnology
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Abstract

The anticoccidial salinomycin is a polyketide produced by Streptomyces albus, and the high-yield strain BK 3-25 produces 18.0 g/L salinomycin under lab condition. In order to elucidate the overproduction mechanism, the genome of BK 3-25 was fully sequenced and compared with the wild-type DSM 41398. Strain BK 3-25 has a 75-kb large deletion, containing type-I polyketide gene cluster PKS-9, and 60 additional InDels and SNVs affecting 55 CDSs, including a 1-bp deletion in type-I PKS gene cluster PKS-6. Subsequently, individual or combined deletions of the 75-kb region and PKS-6 in the wild-type resulted in improved salinomycin yields from 2.60 to 5.20, 6.90, and 9.50 g/L (53% of BK 3-25), respectively, suggesting a redirected flux of polyketide precursors to salinomycin biosynthesis. Moreover, due to the much higher transcription of salinomycin biosynthetic genes (sln) in the high-yield BK 3-25 than in the wild-type, 13 putative regulatory genes among the 55 CDSs were individually inactivated and 7 were proved to be negatively involved in the transcription of sln genes. Combined deletions of two major negative regulatory genes SLNWT_3357 and SLNWT_7015 caused further improved transcription of sln genes as well as the yield, from 2.60 to 7.30 g/L (40% of BK 3-25). Therefore, the comparative genomics approach combined with functional experiments identified that the multiple deletions and mutations of competing gene clusters and negative regulatory genes are crucial for salinomycin overproduction, setting an example for rational titer improvement of other polyketide natural products.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 21661140002, 31470157, 31400030, 31401056) and the Ministry of Science and Technology of China (Nos. 2012CB721005, 2012AA022107, 2012AA02A706). We are grateful to Prof. Yongquan Li (Zhejiang University) and Zhejiang Shenghua Biok Biology Co., Ltd. for providing the strain S. albus BK 3-25.

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  1. Xiaojie Zhang and Chenyang Lu contributed equally to this work.

Authors and Affiliations

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

    Xiaojie Zhang, Chenyang Lu & Linquan Bai

  2. School of Marine Sciences, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, China

    Chenyang Lu

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  1. Xiaojie Zhang
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Correspondence to Linquan Bai.

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Zhang, X., Lu, C. & Bai, L. Mechanism of salinomycin overproduction in Streptomyces albus as revealed by comparative functional genomics. Appl Microbiol Biotechnol 101, 4635–4644 (2017). https://doi.org/10.1007/s00253-017-8278-5

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