Stimulation of the production of macrolide antibiotics by magnesium phosphate and related insoluble materials.

Sir: Biosynthesis of antibiotics is often regulated by carbon catabolites, nitrogen catabolites, phosphates and other metabolites1,2). Recent advances revealed the biochemical bases of the carbon catabolite regulation3.4) and the phosphate regulation5,6). High production of antibiotics has generally been achieved by cultivating the producing organisms in media containing slowly utilized carbon and/or nitrogen sources or under conditions which allow a slow supply of these nutrients1). Although several papers suggested nitrogen catabolite regulation in the biosynthesis of antibiotics1, 2), the importance and the methods for its relief have not been discussed in relation to antibiotic production. Recently, it was reported7) that microbial conversion of glycine to L-serine was stimulated by magnesium phosphate (MgP), and the relevance of the stimulation to the nitrogen catabolite regulation was postulated, based upon the fact that the ammonium ion concentration in the culture broth was depressed in the presence of MgP. In view of this observation it was of interest to examine if MgP might exert a similar effect on the production of antibiotics. The marked stimulation of leucomycin production by MgP has been reported from this laboratory8). The present communication describes the stimulation of the production of other macrolide antibiotics, spiramycin and tylosin, in the presence of MgP and related insoluble materials. Streptomyces kitasatoensis KA-429 (a mutant strain of the original leucomycin producer NRRL 2486), S. ainbofaciens ATCC 23877 (a spiramycin producer), and S. fradiae KA-427 (a tylosin producer) were cultivated at 27'C with reciprocal shaking (240 strokes/min) in a large test tube (20 cm x 2 cm) containing 10 nil of a complex medium or chemically defined medium. The compositions of these media are given in the footnote of Table 1. Antibiotic titer was estimated by conventional paper disc method using