文献类型：期刊文献

英文题名：Balancing nitrogen metabolism to efficiently drive anti-tuberculosis ilamycins biosynthesis in Streptomyces atratus

作者：Zheng, Gaofan[1];Zhou, Weiyan[1];Gui, Yingyue[1];Jiang, Yuxi[1];Zhu, Yunfei[1];Ma, Junying[5];Ju, Jianhua;Xin, Xiujuan[1];Li, Baoli[6,7];Wang, Ruida[1,3];Zhao, Ming[2];An, Faliang[1,4]

机构：[1]East China Univ Sci & Technol, Sch Biotechnol, State Key Lab Bioreactor Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China;[2]Anhui Polytech Univ, Coll Biol & Food Engn, Anhui Engn Lab Ind Microbiol Mol Breeding, Wuhu 241000, Peoples R China;[3]East China Univ Sci & Technol, Sch Biotechnol, Dept Appl Biol, 130 Meilong Rd, Shanghai 200237, Peoples R China;[4]Marine Biomed Sci & Technol Innovat Platform Lin G, 4,Lane 218,Haiji Sixth Rd, Shanghai 201306, Peoples R China;[5]Chinese Acad Sci, CAS Key Lab Trop Marine Bioresources & Ecol, Guangdong Key Lab Marine Mat Med, RNAM Ctr Marine Microbiol,South China Sea Inst Oc, Guangzhou 528225, Peoples R China;[6]Hainan Univ, Sch Pharmaceut Sci, Key Lab Trop Biol Resources Minist Educ, Haikou 570228, Peoples R China;[7]Hainan Univ, Hainan Engn Res Ctr Drug Screening & Evaluat, Sch Pharmaceut Sci, Haikou 570228, Peoples R China

年份：2025

卷号：437

外文期刊名：BIORESOURCE TECHNOLOGY

收录：;EI(收录号：20253218948280);WOS:【SCI-EXPANDED(收录号:WOS:001582914300001)】；

基金：This work was financially supported by the National Key R&D Program of China (Nos. 2023YFA0914102, 2019YFC0312504), National Natural Science Foundation of China (81803381) and Anhui Natural Science Foundation (grant number 2408085QC080). This work was also supported by the Open Research Fund Program of State Key Laboratory of Bioreactor Engineering and Shanghai Collaborative Innovation Center for Biomanufacturing Technology.

语种：英文

外文关键词：Ilamycins; Anti-tuberculosis; Nitrogen metabolism balance; RNA sequencing; S. atratus SCSIO ZH16

摘要：The deep-sea-derived Streptomyces atratus SCSIO ZH16 is a promising host for producing nanomole-level antituberculosis ilamycins. However, limited research on regulating the ilamycins biosynthetic gene cluster (BGC) has hindered industrial production. Our previous study found that nitrogen metabolism-related genes were upregulated in strains with enhanced ilamycins production. Since amino acids from nitrogen metabolism are key precursors, we aimed to optimize ilamycins production by balancing BGC expression and nitrogen metabolism. Using RNA-seq and hierarchical clustering, we identified the native promoter P20605 and its modified version P20605-400, which regulate the positive regulator IlaB in ilamycins BGC. To synchronously boost ilamycins synthesis and precursor supply, we analyzed P20605 ' s function via bioinformatics and validated it using an indigoidine biosynthetic model. The engineered strain Delta ilaR::P20605-400-ilaB::PermE*-phoP achieved over a dozen-fold increase in ilamycins yield. Fermentation was successfully scaled up in 5-L and 500-L bioreactors, reaching titers of 2,546.4 mg/L and 1,993.9 mg/L, respectively, significantly surpassing previously reported yields. This study highlights the industrial potential of ilamycins and provides insights into enhancing peptide compound production in Streptomyces.