Continuous production of thienamycin in immobilized cell systems

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Abstract
A novel 2-L bubble column was used to study the continuous, immobilized cell production of thienamycin. Cells of Streptomyces cattleya were immobilized by culturing them in an appropriate growth medium containing 60/80 mesh celite particles. The dilution rate used during the continuous growth phase was 0.2 h−1. This growth phase was terminated upon the development of heavy cell films (100–500 μm thickness), and the medium was replaced with an appropriate thienamycin production medium. The system was then operated in a batch mode until thienamycin production began. At that time, continuous feeding of the production medium was initiated and the influence of medium composition and dilution rate on CO2, NH4, biomass, and thienamycin production investigated. With synthetic production medium, a doubling of the dilution rate from 0.05 to 0.10 h−1 resulted in a doubling of the thienamycin volumetric productivity. Rates of CO2 and NH4 production increased by ca. factors of three and two, respectively. The rate of PO4 utilization also doubled. When the dilution rate was decreased to 0.05 h−1, the rates of CO2 production and PO4 utilization quickly decreased (i.e., within 3 h). The rates of NH4 and thienamycin production also decreased but more slowly (i.e., ca. 100 h after the decrease in dilution rate). With complex production medium, the rates of CO2 production and PO4 utilization appeared to be a direct function of dilution rate at the dilution rates tested. Thienamycin production in this case was not a function of dilution rate. Comparing the synthetic medium with the complex medium at either dilution rate, the volumetric rate of thienamycin production was higher in the system being fed complex medium. However, the specific activity (units thienamycin/g cell/h) observed with complex medium was lower than that observed with synthetic medium. The higher volumetric productivity observed with complex medium was the result of a high cell loading. The above observations will be discussed in terms of control of thienamycin synthesis and film thickness effects.