A STRUCTURED MODEL FOR HYPHAL DIFFERENTIATION AND PENICILLIN PRODUCTION USING PENICILLIUM-CHRYSOGENUM

A structured kinetic model describing growth, differentiation, and pen icillin production in submerged Penicillium chrysogenum fermentations is reported. The filamentous hyphae are divided into four distinct reg ions on the basis of the activities and structure of hyphal compartmen ts, viz., actively growing (mainly apical) regions, nongrowifig or pen icillin producing regions, vacuoles, and degenerated or metabolically inactive regions. A mechanistic approach is taken to give quantitative descriptions of differentiation and degeneration as a consequence of vacuolation. The growth and degeneration of vacuoles are expressed in the form of a population balance. The model assumes that newly generat ed vacuoles appear by differentiation of healthy regions, grow in size with limitation of available substrate, and eventually give rise to e mpty hyphal compartments. In the model the penicillin production is re lated to the amounts of the nongrowing regions of the hyphae. The mode l is used for successful predictions of the amounts of the four hyphal regions and the penicillin G production rate throughout the fed-batch fermentations of an industrial P. chrysogenum strain under different glucose feeding regimes. Quantitative information on proportions of th e hyphal regions was obtained from image analysis measurements and the parameters of the kinetic model were identified. When the glucose fee d rate to the production culture is switched between a high and a low value, the model can successfully predict the dynamic changes of diffe rentiation and the resulting penicillin production caused by the varia tions in the nutrient conditions. The use of image analysis to charact erize differentiation as a basis for structured modeling of the penici llin fermentation appears to be very powerful, and the method has grea t potential for use in process simulation and control of antibiotic fe rmentations. (C) 1996 John Wiley & Sons, Inc.