文献类型：期刊文献

英文题名：Systematic engineering of Micromonospora echinospora cell factory for gentamicin C1a overproduction

作者：Xu, Feng[1,2,3];Gao, Hao[1,2];Ben, Rong[1,2];Hu, Kaihao[1,2];Wang, Yuan[1,2];Mohsin, Ali[1,2];Guo, Yuanxin[1];Li, Xu[1];Hang, Haifeng[1,2,3];Chu, Ju[1,2,3];Tian, Xiwei[1,2,3]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Qingdao Innovat Inst, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Natl Ctr Bioengn & Technol Shanghai, Shanghai 200237, Peoples R China;[3]East China Univ Sci & Technol, Shanghai Collaborat Innovat Ctr Biomfg Technol, Shanghai 200237, Peoples R China

年份：2026

卷号：44

期号：5

起止页码：1398

外文期刊名：TRENDS IN BIOTECHNOLOGY

收录：;EI(收录号：20260419946884);WOS:【SCI-EXPANDED(收录号:WOS:001765064500004)】；

基金：This work was financially supported by the National Key Research and Development Program of China (2024YFA0917900) , the Taishan Scholars Program of Shandong Province (No. tsqn202312316) , the Shanghai Pilot Program for Basic Research (22TQ1400100-14) , the Natural Science Foundation of Shanghai (23ZR1416500) , and the Frontiers Science Center for Materiobiology and Dynamic Chemistry (JKVJ1231036) . The authors also thank the Arawana Charity Foundation for the financial support.

语种：英文

外文关键词：Antibiotics - Biochemistry - Biosynthesis - Genes - Metabolism - Optimization

摘要：The clinical importance of gentamicin C1a as a broad-spectrum aminoglycoside antibiotic underscores the need for efficient biomanufacturing strategies. In this study, we developed a systematic engineering framework to enhance gentamicin C1a production. First, a genome-scale metabolic model (iFX1172) was reconstructed to pinpoint critical bottlenecks in both regulatory and biosynthetic pathways. Guided by model predictions and experimental validation, we identified genC, metK, and BldD as synergistic targets. Coordinated overexpression of these genes increased gentamicin C1a titers to 198.1 mg/L, representing a 34.3% improvement over the parental strain, and also enhanced the titers of other aminoglycoside antibiotics by up to 1.6-fold, demonstrating the universality of the strategy. Metabolic flux analysis and targeted metabolomics revealed that redox homeostasis and ATP availability are pivotal for biosynthesis. Finally, process optimization in a fed-batch bioreactor using a Bayesian framework, coupled with in situ resin adsorption, yielded 964.1 mg/L gentamicin C1a with a yield of 24.1 mg/g glucose and a productivity of 6.7 mg/L/h.