文献类型：期刊文献

英文题名：Prelude to rational scale-up of penicillin production: a scale-down study

作者：Wang, Guan[1];Chu, Ju[1];Noorman, Henk[2];Xia, Jianye[1];Tang, Wenjun[1];Zhuang, Yingping[1];Zhang, Siliang[1]

机构：[1]E China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]DSM Biotechnol Ctr, NL-2600 MA Delft, Netherlands

年份：2014

卷号：98

期号：6

起止页码：2359

外文期刊名：APPLIED MICROBIOLOGY AND BIOTECHNOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000332108100001)】；

基金：This work was financially supported by Major State Basic Research Development Program of China (973 Program, 2013CB733600), NWO-MoST Joint Program (2013DFG32630), and the National Scientific and Technological Major Special Project (Significant Creation of New Drugs, no. 2011ZX09203-001-03).

语种：英文

外文关键词：Scale-down; Scale-up; Gradients; Model; Computational; Penicillin; P. chrysogenum

摘要：Penicillin is one of the best known pharmaceuticals and is also an important member of the beta-lactam antibiotics. Over the years, ambitious yields, titers, productivities, and low costs in the production of the beta-lactam antibiotics have been stepwise realized through successive rounds of strain improvement and process optimization. Penicillium chrysogenum was proven to be an ideal cell factory for the production of penicillin, and successful approaches were exploited to elevate the production titer. However, the industrial production of penicillin faces the serious challenge that environmental gradients, which are caused by insufficient mixing and mass transfer limitations, exert a considerably negative impact on the ultimate productivity and yield. Scale-down studies regarding diverse environmental gradients have been carried out on bacteria, yeasts, and filamentous fungi as well as animal cells. In accordance, a variety of scale-down devices combined with fast sampling and quenching protocols have been established to acquire the true snapshots of the perturbed cellular conditions. The perturbed metabolome information stemming from scale-down studies contributed to the comprehension of the production process and the identification of improvement approaches. However, little is known about the influence of the flow field and the mechanisms of intracellular metabolism. Consequently, it is still rather difficult to realize a fully rational scale-up. In the future, developing a computer framework to simulate the flow field of the large-scale fermenters is highly recommended. Furthermore, a metabolically structured kinetic model directly related to the production of penicillin will be further coupled to the fluid flow dynamics. A mathematical model including the information from both computational fluid dynamics and chemical reaction dynamics will then be established for the prediction of detailed information over the entire period of the fermentation process and thereby for the optimization of penicillin production, and subsequently also benefiting other fermentation products.