Widespread activation of antibiotic blosynthesis by S-adenosylmethionine in streptomycetes

The effect of S-adenosylmethionine (SAM) on the production of various antibiotics was investigated to determine whether SAM dpendent methylation is required in biosynthetic pathways of antibiotics. Pristinamycin dependent methylation IN and granaticin do not require SAM-dependent methylation in their biosynthesis pathways, and production of these two antibiotics was increased about 2-fold when a low concentration (50 and 10 muM, respectively) of SAM was treated; in contrast, oleandomycin and avermectin B1a require SAM as a methyl donor in their biosynthesis, and production of these two antibiotics was increased 5-fold and 6-fold, depending on the SAM concentration within a certain range. We also found that the transcription of a pathway-specific regulator, gra-ORF9, was activated by exogenous SAM treatment. Production of oleandomycin and avermectin B1a was decreased by using a methyltransferase inhibitor, sinefungin, but the production levels of these antibiotics were restored to the control level by simultaneously adding SAM and sinefungin. Interestingly, we have found a similar stimulatory effect of S-adeiiosylhomocysteine (SAH), the methylation product of SAM, on antibiotic production in the four strains. Our results clearly demonstrate the widespread activation of antibiotic production using SAM in streptomycetes. (C) 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.