Metabolic Comparative Analysis Of The Differing Feeding Strategies And Application Of Computational Fluid Dynamics To The Flow Field Study For The Optimization Of Cephalosporin C Fermentation Process

Currently, the cephalosporins were one of the anti-infective drugs which are being widely applied in clinical treatment, they also have a good market share; hence, there were intense competition in the industrial productions of cephalosporins and cephalosporin C (CPC).The metabolic researches for two fed-batch fermentations with different feeding modes were conducted with the help of marco-metabolic analysis and cross-scale parameters correlation analysis. An increase of 11.4% in biomass was observed with the optimized feeding compared to the original one, together with a 20% increase of the CPC formation rate in the period of 55-87h. The drop of dissolved oxygen below to 30%, which always occurred in the original feeding process, was overcome in the optimized feeding process. The comparison of the amino acids consumption indicated that faster consumption of methionine and serine during rapid CPC formation phase was observed in the optimized feeding process. Higher level of intracellular a-KG and pyruvate was also observed in this feeding process, which had improved the biosynthesis of valine and a-AAA. Hence, relatively abundant supply of precursors in CPC biosynthesis was present in the optimized feeding process.Quantitative metabolic analysis confirmed the view that optimized feeding process in the rapid CPC formation phase had stronger supply of precursors; the fluxes through valine and a-AAA formation were higher than that of control with 6.9% and 6.7% increase respectively, corresponding increased CPC formation flux of 15.1% was observed. The generation and consumption of NADPH, ATP indicated that higher utilization of NADPH and ATP in the optimized feeding process was present; higher CPC production was obtained in the period of 63-95h although the generations of NADPH and ATP were lower than those of control with degree of 42.5% and 16.3%, respectively. Meanwhile, the consumption of NADPH and ATP also provided us with the useful clue for further optimization of CPC fermentation process.Simulation by computational fluid dynamics for rheological characteristics study in the 12t fermentor with four Rushton turbine impellers found that there was mixing inequality and serious stratification between impellers layers, while the rheological characteristics with new designed impellers was improved significantly, which can be confirmed by the determination results of soybean oil. The comparative analysis of rheological distribution at 23h and the process metabolic analysis indicated that new designed impellers didn't affect the growth of A.chrysogenum, and this novel impeller combination had relatively mild mechanical shear, mixing equality in axial flow, uniform bubbles dispersion. What's more important was the lower energy consumption with a decrease of 29.5% compared to the control.