Antibiotics optimizing fermentation processes

In biotechnological processes effective exploitation of raw materials and high yields can be gained by process control involving on-line determination of a multitude of parameters. In fermentation processes, e.g., of antibiotics, a certain time course of the concentration of such nutrients as carbohydrates, amino acids, phosphates, and ammonium, as well as hormones has to be followed closely. The determination of these substances is therefore an indispensable prerequisite for optimization of the product yield. Knowledge of the product concentration permits direct evaluation of the state of the bioprocess. Table 25 gives an overview of the value of biotechnological products and points to the potential areas of biosensor application in fermentation and cell culture media. 

The examples presented have shown that the construction of simple unstructured models based on some notion of relevant kinetic equations in combination with the very important concept of elemental composition and enthalpy balance is of great help in understanding factors relevant in the optimization and control of even such complex fermentation processes as the production of antibiotics. 

Fermentation temperature Enzyme stability and acceleration of chemical reactions show opposite temperature dependencies, resulting in a distinct temperature optimum of the underlying fermentation process. Examples such as the fermentative production of the antibiotic viomycin show that this temperature range for optimal production rates might be quite small (viomycin production 25 °C -523 mg/L, 30 °C - 657 mg/L 37 °C - 0 mg/L). Since microbial degradation of the already-formed product is governed by the same principle, the conditions (temperature, incubation time) for netto formation (= actual isolable amount) needs to be optimized. As an example, for the microbial production of... 

Occurrence, Fermentation, and Biosynthesis. Although a large number of Streptomjces species have been shown to produce carbapenems, only S. cattkja (2) and S. penemfaciens (11) have been reported to give thienamycin (2). Generally the antibiotics occur as a mixture of analogues or isomers and are often co-produced with penicillin N and cephamycin C. Yields are low compared to other P-lactams produced by streptomycetes, and titres are of the order of 1—20 p-g sohdusmL despite, in many cases, a great deal of effort on the optimization of the media and fermentation conditions. The rather poor stabiUty of the compounds also contributes to a low recovery in the isolation procedures. The fermentation and isolation processes for thienamycin and the olivanic acids has been reviewed in some detail (12). 

Despite the ever-increasing use of complex instrumentation, the application of feedback control techniques and the use of computers, the science of antibiotic fermentation is still imperfectly developed. Processes are difficult to optimize and no two apparently identical batches will ever be entirely the same. This is because living cell populations change both quantitatively and qualitatively throughout the production cycle and small changes in control parameters, such as a fluctuation in air pressure or a power dip, can potentially impact a batch and the effect may vary dependent upon the age of the batch. Also there tends to be significant batch to batch variation in the complex nutrients commonly used in the fermentations. 

TLC and its modem modifieation, high-performance thin-layer chromatography (HPTLC), introdueed in 1975 (2), are used in various fields of the antibiotic industry, including strain improvement, optimization of fermentation, product isolation, process control, pharmacokinetics, and in control laboratories as well. A shortcoming of HPTLC, its high detection limit in comparison to... 

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