Transcriptome-guided identification of a four-component system, SbrH1-R, that modulates milbemycin biosynthesis by influencing gene cluster expression, precursor supply, and antibiotic efflux

文献类型： 外文期刊

第一作者： Ye, Lan

作者： Ye, Lan;Wang, Xiangjing;Xiang, Wensheng;Ye, Lan;Zhang, Yanyan;Li, Shanshan;He, Hairong;Xiang, Wensheng;Ai, Guomin;He, Hairong

作者机构：

关键词： Milbemycins; Streptomyces bingchenggensis; SbrH1-R; Precursor supply; Milbemycin exporter; Overproduction

期刊名称：SYNTHETIC AND SYSTEMS BIOTECHNOLOGY （ 影响因子：4.692； 五年影响因子：5.23 ）

ISSN： 2405-805X

年卷期： 2022 年 7 卷 2 期

页码：

收录情况： SCI

摘要： Streptomyces can produce numerous antibiotics and many other bioactive compounds. Recently, the molecular mechanisms of transcriptional regulators in control of antibiotic production by influencing the expression of biosynthetic gene clusters (BGCs) have been extensively studied. However, for regulators that affect both antibiotic production and cell growth, the way to influence antibiotic production may be diverse, but related studies are limited. Here, based on time-course transcriptome analysis, a four-component system, SbrH1-R, consisting of the two-component system SbrKR (SBI_03479/3478) and two hypothetical proteins SbrH1 (SBI_03481) and SbrH2 (SBI_03480) potentially related with the biosynthesis of milbemycins was identified in Streptomyces bingchenggensis BC-101-4. Deletion of sbrH1-R resulted in weakened cell growth but a 110% increase of milbemycin production compared with that in BC-101-4. Comparative transcriptome analyses of the sbrH1-R mutant and BC-101-4 revealed that SbrH1-R not only indirectly represses milbemycin BGC expression, but also inhibits milbemycin production by modulating expression levels of genes related to precursor supply and antibiotic efflux. Further genetic experiments identified several new targets, including five precursor supply-associated reactions/pathways (e.g., the reaction from pyruvate to acetyl-CoA, the reaction from acetyl-CoA to citrate, the fatty acid beta-oxidation process, and the branched chain amino acid and phenylalanine acid degradation pathways) and a milbemycin exporter system (MilEX2) that can be engineered for milbemycin overproduction. These results shed new light on the understanding of regulation of milbemycin biosynthesis and provide useful targets for future metabolic engineering of the native host to improve milbemycin production.

分类号：

  • 相关文献
作者其他论文 更多>>

微信小程序