The following facts should be taken into account for optimization and scale-up of fermentation processes for the production of ergot alkaloids (Kobel and Sanglier 1978), (a) the production strains should be continually tested to maintain the optimal quality of selected production strain and thus maximally eliminate the biological effects given by transfer of cultures, ageing, and other external influences, (b) long cultivation period in absence of antibiotics require very high standard of sterility in operation and equipment, (c) balanced aeration and stirring are required due to the sensitivity of the Claviceps cultures to the stress and high oxygen tension, and (d) the use of antifoam agents could cause considerable loss in alkaloid yield. Recently the application of oxygen vectors to C. purpurea cultivation was published (Menge et al. 2001). The classical problem of the large-scale fermentations is an optimal supply of oxygen to growing Claviceps sp. High oxygen demand in the exponential growth phase can be met by addition of different hydrocarbons (Gilmanov et al. 1996) or perfluorocarbons (Menge et al. 2001) to shake flask and/or stirred reactors. Perfluorocarbons were successfully applied also in cultivations of other microorganisms (Lowe et al. 1998). Besides these technological aspects, other techniques to optimize the fermentation process were described. The influence of nutrients, addition of ergot alkaloid precursors, mainly tryptophan and its derivatives, were described in many studies (Erge et al. 1984; Floss 1976). As a result of feeding, prolonged idiophase of the fermentation process was found (Milicic et al. 1987) and this process seems to be one of the perspectives in modern alkaloid production (Socic and Gaberc-Porekar 1992). Precursor controlled production of modified ergopeptines was described by Bianchi et al. (1982) and Crespi-Perellino et al. (1992).
The growth of the fungus and alkaloid formation in submerged batch fermentation was described by mathematical model, which can be further used in automatic process control and optimization. Grm et al. (1980) proposed for C. purpurea growth model based on morphological features of a cell population during the fermentation process. Votruba and Pazoutova (1981) proposed another model accentuating the antagonistic effects of phosphate on growth and alkaloid production. A mathematical simulation of different technological alternatives of clavine alkaloid production was done on this basis (Pazoutova et al. 1981). The activation -inhibition kinetics of clavine alkaloids production was evaluated for two C. fusiformis strains (Flieger et al. 1988) and it was found that feed-back inhibition can be eliminated by combination of fermentation and separation units in a closed loop. Increased efficiency (more than 100%) of the fermentation process was also found when inducers of cytochrome P-450 were used (Rylko et al. 1988).
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