s. Therefore, we speak about a physiological state of the whole culture that represents an average of physiological states of the individual cells.
Regulation by nutrients. In order to reach a high production of an antibiotic, a sufficient biomass yield is necessary, that is accomplished within a short time, if possible. Thus a danger of contamination is diminished and the economic parameters of the fermentation device are kept at its optimum. For this purpose, readily utilizable carbon, nitrogen and phosphorus sources are used. When they are present in the medium, however, an overproduction of the antibiotic does not take place. The culture medium should be designed in such a way that, after the biomass increased sufficiently, at least one of the basic nutrient sources would become depleted and the culture growth would be consequently limited. However, this limitation is not well understood.
Regulation by nitrogen source.Readily utilizable nitrogen sources present in the culture medium inhibit the production of antibiotics. Mainly ammonium ions decrease the antibiotic synthesis and, therefore, their concentration in the production media is limited to be exhausted at the end of growth phase. Soy flour, peanut flour and other complex substances are used as nitrogen sources in the production phase of antibiotic fermentations. These nitrogen sources are not easily utilizable and are similar to those used by the microorganisms producing antibiotics in nature. Readily utilizable nitrogen sources repress enzymes of secondary metabolism in Cephalosporium acremonium during the biosynthesis of cephalosporin and in Streptomyces clavuligerus producing cephamycin. Similarly, the inhibition of biosyntheses of leucomycin, tylosin, and erythromycin are explained by the repression of enzymes of secondary metabolism. Ammonium salts also inhibit the activity of anhydrotetracycline oxygenase isolated from S. Aureofaciens.
Regulation by phosphate [19]. Phosphate is used as main regulator of overproduction of antibiotics in factories. Inorganic phosphate is carefully added in doses to the medium so as to accomplish an optimal ratio between the biomass production and the capability of antibiotic biosynthesis. Bound to organic compounds normally added to the medium (soy flour, etc.), phosphate does not affect the antibiotic production. The antibiotic biosynthesis is started on the condition the concentration of phosphate in the medium decreased below a certain level. influence of inorganic phosphate is explained by repression of the synthesis of enzymes of secondary metabolism. After the inorganic phosphate was depleted from the medium, a significant decrease of the rate of proteosynthesis was observed during the tetracycline biosynthesis and the synthesis of enzymes of secondary metabolism was commenced. If phosphate was kept above the threshold concentration, the significant decrease of the rate of protein synthesis did not occur and enzymes of secondary metabolism were not synthesized. An addition of phosphate to the medium at the beginning of the production phase, after the phosphorus source was depleted and the enzymes of secondary metabolism synthesis initiated, resulted in a decrease of the enzyme levels in the culture and an acceleration of proteosynthesis. The synthesis of secondary metabolism was resumed after the phosphate was depleted again from the medium. Production of oxytetracycline by Streptomyces rimosus is controlled, at least in part, at the level of transcription from promoters overlapped by tandem repeats similar to those of the DNA-binding sites of the OmpR family [20]. The phosphate was found to be consumed at a higher rate than expected, with respect to the actual rate of protein synthesis, and was probably deposited in the cells in the form of polyphosphates.
. 2.2 Influence of low molecular compounds
The antibiotic production can be regulated by different low molecular compounds. The mechanism of their action is not understood. Tryptophan exhibited a stimulatory effect on the production of antibiotics, eg mucidin in the basidiomycete Oudemansiella mucida and actinomycin in Streptomyces parvulus. Methionine was found to promote the synthesis of cephalosporin C. Neither tryptophan nor methionine were used as the building units. When enzymes of secondary metabolism were measured, higher levels were detected in the cells of the producing strain.Benzyl thiocyanate increases the production of chlortetracycline and tetracycline in S. aureofaciens. In contrast, it does not influence the production of oxytetracycline in S. rimosus. The effect on the metabolism of S. aureofaciens is multiple, including a number of enzymes but the basic influence of benzylthiocyanate at production is the higher expresion of enzymes of secondary metabolism....
