| In this study, several aspects of the physiological regulation of tylosin biosynthesis in Streptomyces fradiae, strain C373.1 are examined. As with most secondary metabolite fermentations, tylosin biosynthesis involves a sequence of many metabolic reactions with complex (and several unknown) regulatory elements. So far, structural gene cloning approaches were of limited success. The general philosophy of the approach in this dissertation is based on the expectation that exploring and identifying specific regulatory elements could lead to more rational strategies for improvement of fermentation efficiencies. The approaches are based on the present state of knowledge of the genetics, biochemistry, and physiology of tylosin fermentation.; The role of several carbon sources on the growth and antibiotic production are examined. Glucose and galactose repress tylosin production severely, but reversibly, probably by repression of fatty acid metabolism which is required for tylosin synthesis. Yet, glucose or other six carbon sugars seem to be required for good productivity. Mannitol facilitates simultaneous production with growth. Several mutants that could grow in the presence of high concentrations of 2-deoxyglucose were isolated. Some of these mutants produce elevated levels of tylosin compared with the wild-type culture. Cyclic AMP was found to play a role in the secondary metabolism of the organism. In nutritionally lean media, cyclic AMP caused a low level stimulation of antibiotic production while in rich media, a dramatic differentiation response was observed. Based on the observed physiology of the fermentation, a case is presented for a steady-state, two-stage continuous fermentation for the realization of increased tylosin titers. Numerical simulation results are presented to this effect. |
