Artificial intelligence-guided fermentation process regulation reveals metabolic rewiring in gentamicin C1a overproduction

Feng Xu; Lihuan Su; Yuan Wang; Hao Gao; Kaihao Hu; Rong Ben; Yuanxin Guo; Xu Li; Ju Chu; Xiwei Tian

doi:10.1016/j.biortech.2025.132968

Artificial intelligence-guided fermentation process regulation reveals metabolic rewiring in gentamicin C1a overproduction

Bioresour Technol. 2025 Jul 10:436:132968. doi: 10.1016/j.biortech.2025.132968. Online ahead of print.

Authors

Feng Xu¹, Lihuan Su², Yuan Wang², Hao Gao², Kaihao Hu², Rong Ben², Yuanxin Guo², Xu Li³, Ju Chu¹, Xiwei Tian⁴

Affiliations

¹ State Key Laboratory of Bioreactor Engineering, Qingdao Innovation Institute of East China University of Science and Technology, East China University of Science and Technology, Shanghai 200237, China; National Center of Bio-Engineering & Technology (Shanghai), East China University of Science and Technology, Shanghai 200237, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai 200237, China.
² State Key Laboratory of Bioreactor Engineering, Qingdao Innovation Institute of East China University of Science and Technology, East China University of Science and Technology, Shanghai 200237, China; National Center of Bio-Engineering & Technology (Shanghai), East China University of Science and Technology, Shanghai 200237, China.
³ State Key Laboratory of Bioreactor Engineering, Qingdao Innovation Institute of East China University of Science and Technology, East China University of Science and Technology, Shanghai 200237, China. Electronic address: xli@ecust.edu.cn.
⁴ State Key Laboratory of Bioreactor Engineering, Qingdao Innovation Institute of East China University of Science and Technology, East China University of Science and Technology, Shanghai 200237, China; National Center of Bio-Engineering & Technology (Shanghai), East China University of Science and Technology, Shanghai 200237, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai 200237, China. Electronic address: xiweitian@ecust.edu.cn.

PMID: 40651707
DOI: 10.1016/j.biortech.2025.132968

Abstract

In this study, an integrated optimization framework that combined artificial neural network-genetic algorithm (ANN-GA) modeling, multi-sensor online monitoring, and metabolic profiling was developed. The ANN-GA model outperformed the traditional methods in terms of prediction accuracy, exhibiting superior fitting capability and enhanced performance of gentamicin C1a production. Real-time fermentation control was achieved via integrated near-infrared and Raman spectroscopy, yielding a 54.6 % titer increase (385.3 mg/L) over control group (249.2 mg/L). Metabolomic and metabolic flux analyses revealed a 36.2 % and 18.4 % reduction in glycolysis and tricarboxylic acid cycle fluxes, respectively, with an 11.3 % increase in pentose phosphate pathway flux and enhanced NADPH availability. Carbon flux was redirected toward biosynthetic intermediates, with key precursor pools such as glucose-1-phosphate and gentamicin X2 increasing by 52.8 % and 61.7 %, respectively. Overall, the approach significantly enhanced gentamicin C1a titer and laid the foundation for a scalable paradigm and theoretical framework for the intelligent optimization of industrial bioprocesses.

Keywords: Artificial neural network; Fermentation optimization; Genetic algorithm; Metabolic flux analysis; Multi-sensor monitoring.