Strain Improvement

Strain improvement using a mutation/selection programme (Chapter 3) for improving an organism being used in an established process or a potential process can be very cost effective. Historically, mutation/selection programmes to improve strains of Pénicillium chrysogenum were time consuming, labour intensive and very random because of the lack of knowledge about penicillin biosynthesis. These mutation programmes did, however, contribute significantly to increases in penicillin yields from less than 100 units cm"3 in the 1940s to over 51,000 units cm^3 by 1976 (Queener and Swartz, 1979) and a four-fold increase in yields between 1970 and 1985 at Gist Brocades (Royce, 1993). Improvements for streptomycin, chlortetracy-cline and erythromycin are reported in Table 3.8.

It is always very important to decide if a strain improvement programme can be justified on financial grounds to improve the overall economy of a process. Lockwood and Streets (1966) quoted the example of a fermentation process making 453,600 kg year"1 of product at 23.5 p kg-1 in which a 1% increase in the product would produce an increased return of only £1070, which they considered insufficient to support a worthwhile mutation programme. If the output had been 10 times greater, a 1% increase would have produced £10,700 which was thought to be just sufficient to meet the costs of research. If this output could have been increased to 10%, the increased return would have been £107,000, which would have been much larger than the cost of a mutation programme at that time. Calam (1969) suggested that a graduate worker with two assistants are capable of operating one or two mutation research programmes and of making effective progress.

A better understanding of cell metabolism and its regulation has enabled the development of more logical targeted methods to be introduced to select for mutants with desirable 'blue prints' where there may be a need to block undesirable enzyme activities or eliminate negatively acting control mechanisms (Chapter 3). This approach is much more efficient and economic in terms of resources and time. It was first employed extensively in the preparation of mutant strains used in amino acid fermentations.

Although the main targets in strain improvement are normally to increase the product yield or specific production rates, it is also important to consider strain stability, resistance to phage infection, response to dissolved oxygen, tolerance to medium components, production of foam and the morphological form of the organism. Methods to achieve many of these changes are discussed in Chapter 3. These are very important in helping to achieve targets in a research and development programme as they can have a significant impact on the process and/or product (Table 12.2). A study of the range of targets given in this table, which might be aided by strain improvement, has economic effects on all aspects of a fermentation process.

There are a number of companies with special expertise, such as Cetus Ltd and Panlabs Inc., who will perform strain-development programmes or make cultures available for commercial clients. An example of work by Panlabs Inc.'s improvements in yields of penicillin from cultures of P. chrysogenum during 1973 to 1976 is shown in Table 12.3 (Queener and Swartz, 1979). These data make it possible to compare yields from the same culture cultured at various scales.

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