Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, P. R. China.
Hubei Engineering Laboratory for Synthetic Microbiology, Wuhan Institute of Biotechnology, Wuhan 430075, P. R. China.
Biotechnol J. 2019 Jan;14(1):e1700769. doi: 10.1002/biot.201700769. Epub 2018 Jul 5.
Spinosad is a potent insecticide that exhibits an excellent environmental and mammalian profile. However, spinosad production in the original producer, Saccharopolyspora spinosa, is insufficient for the huge global demand. Great efforts have been exerted to improve the production of spinosad. Strategies for spinosad overproduction in actinomycetes are reviewed in this article, including metabolic engineering of the precursor and spinosyn biosynthetic pathway, introduction of regulatory genes, genome-scale metabolic model-guided engineering, mutagenesis, genome shuffling, fermentation process optimization, omics analysis, and the heterologous biosynthesis of spinosad in other actinomycetes. Furthermore, highly productive industrial strains should be used as heterologous hosts for enhancing spinosad biosynthesis in the future. To accelerate the engineering process, the CRISPR/Cas9 system should be established in Sa. spinosa for large-scale genome editing. Notably, the regulatory mechanism of spinosad biosynthesis remains unclear. Thus, the combining multi-omics analysis with high-throughput screening of chemical elicitors would be a promising approach in characterizing the regulatory and signal transduction mechanisms and improving spinosad production in Sa. Spinosa.
多杀菌素是一种高效杀虫剂，具有极好的环境和哺乳动物安全性。然而，原始生产菌棘孢小单孢菌（Saccharopolyspora spinosa）的多杀菌素产量无法满足全球巨大的需求。因此，人们做出了巨大的努力来提高多杀菌素的产量。本文综述了放线菌中多杀菌素过量生产的策略，包括前体和多杀菌素生物合成途径的代谢工程、调控基因的引入、基于基因组尺度代谢模型的工程设计、诱变、基因组重排、发酵过程优化、组学分析以及其他放线菌中的多杀菌素异源生物合成。此外，未来应该使用高产的工业菌株作为异源宿主来增强多杀菌素的生物合成。为了加速工程进程，应该在棘孢小单孢菌中建立 CRISPR/Cas9 系统以进行大规模基因组编辑。值得注意的是，多杀菌素生物合成的调控机制仍不清楚。因此，将多组学分析与化学诱导剂的高通量筛选相结合，可能是表征调控和信号转导机制并提高棘孢小单孢菌中多杀菌素产量的有前途的方法。
