[Directed synthesis of macrotetrolides].

The composition of the macrotetrolide complex was found to be strongly dependent on the conditions of the Streptomyces chrysomallus v. macrotetrolidi cultivation and could be varied by including in the medium 0.2% of organic acids, precursors of macrotetrolides, such as acetic, propionic and succinic. Acetate caused an increase of the nonactin/monactin ratio, and no other homologues were detected. On the contrary, propionate and succinate produced a drop in the nonactin synthesis, which was accompanied by a rise in the amount of the higher homologues. The composition of the macrtetrolide mixture can also be changed by introducing in the cultivation medium specific inhibitors (100-200 micrograms/ml) such as malonate, cobalamin analogue, sulfadimesin. Malonate, an inhibitor of succinate dehydrogenase, increased the biosynthesis of higher ethylated homologues. Inhibition of methylmalonate mutase resulted in an increased yield of the methylated nonactin homologue and in a decreased yield of dinactin. In this case no other homologues were produced. The inhibitor of transmethylation, sulfadimesin, had no effect on the biosynthesis and composition of the macrotetralide mixture.