Stepwise increase of thaxtomins production in Streptomyces albidoflavus J1074 through combinatorial metabolic engineering |
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| Affiliation: | 1. Biotechnology Research Center, Southwest University, Chongqing, 400715, China;2. Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, Southwest University, Chongqing, 400715, China;3. State Cultivation Base of Crop Stress Biology for Southern Mountainous Land, Academy of Agricultural Sciences, Southwest University, Chongqing, 400715, China;1. Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan;2. Manchester Institute of Biotechnology, Manchester Synthetic Biology Research Centre SYNBIOCHEM, Department of Chemistry, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK;1. Institute of Pharmaceutical Biotechnology, School of Medicine and the Children’s Hospital, Zhejiang University, Hangzhou, 310058, China;2. The First Affiliated Hospital, Zhejiang University School of Medicine, 310058, China;3. Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Hangzhou, 310058, China;1. Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, People''s Republic of China;2. SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People''s Republic of China;1. Department Microbial Natural Products, Actinobacteria Metabolic Engineering Group, Saarland University, Campus C2.3, 66123 Saarbrücken, Germany;2. Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infectious Research (HZI), Germany;3. i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal;4. IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal;1. National Glycoengineering Research Center, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, PR China;2. CAS Key Lab of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, PR China |
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| Abstract: | 
Herbicide-resistance in weeds has become a serious threat to agriculture across the world. Thus, there is an urgent need for the discovery and development of herbicides with new modes of action. Thaxtomin phytotoxins are a group of nitrated diketopiperazines produced by potato common scab-causing phytopathogen Streptomyces scabies and other actinobacterial pathogens. They are generally considered to function as inhibitors of cellulose synthesis in plants, and thus have great potential to be used as natural herbicides. Generation of an overproducing strain is crucial for the scale-up production of thaxtomins and their wide use in agriculture. In the present study, we employed a stepwise strategy by combining heterologous expression, repressor deletion, activator overexpression, and optimization of fermentation media for high-level production of thaxtomins. The maximum yield of 728 mg/L thaxtomins was achieved with engineered Streptomyces albidoflavus J1074 strains in shake-flask cultures, and it was approximately 36-fold higher than S. albidoflavus J1074 carrying the unmodified cluster. Moreover, the yield of thaxtomins could reach 1973 mg/L when the engineered strain was cultivated in a small-scale stirred-tank bioreactor. This is the highest titer reported to date, representing a significant leap forward for the scale-up production of thaxtomins. Our study presents a robust, easy-to-use system that will be broadly useful for improving titers of bioactive compounds in many Streptomyces species. |
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| Keywords: | Thaxtomin Heterologous expression |
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