Reevaluation of the Final Steps in the Biosynthesis of Blasticidin S by Streptomyces griseochromogenes and Identification of a Novel Self-Resistance Mechanism

The final steps in the biosynthesis of the antifungal peptidyl-nucleoside blasticidin S (3) have been revised to include a novel self-resistance mechanism wherein the previously proposed final precursor, demethylblasticidin S (7), is modified with a leucine residue yielding leucyldemethylblasticidin S (10) which exhibits reduced antibiotic activity. Methylation of 10 yields leucylblasticidin S (9) which can be exported from the bacterium and hydrolyzed to 3. Also disclosed is the finding of a blasticidin S N-acetyltransferase activity that may function to detoxify 3 and 7 inadvertently produced prior to export or which gain reentry to the cell.