|Budget Amount *help
¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 1991: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1990: ¥4,600,000 (Direct Cost: ¥4,600,000)
It was the first aim of this study to clarify bio-organic-chemically the biosynthetic process of macrolide antibiotics (especially, oleandomycin) by testing the incorporation of their aglycones, which were presumed to be biosynthetic precursor, to blocked mutants of an oleandomycin-producing organism, Streptomyces antibiotics. The second was the preparation of new macrolide antibiotics by the incorporation of unnatural aglycones.
The proposed aglycone-presusors, (8RO-8, 8a-deoxyoleandolide(2), (8R, 9S)-9-dihydro-8, 8a-deoxyoleandolide(3), (9R)-9-dihydro-8, 8a-dehydro-8, 8a-deoxyoleandolide(4), 8, 8a-dehydro-8, 8a-deoxyoleandolide(5)and oleandolide(6)were synthesized from oleandomycin(1). The incorporation of tmese aglycones to mutants, which were prepared by us, was assayed by identification of produced antibiotics with 1 using HPLC and antibiotic activities. The aglycones 5 and 6 were most efficiently incorporated to produce 1, but the others were done to a lesser extent. This opens the possibility that a logical biosynthetic pathway would be 2->3->4->5->6->1.
On the other hand, other chemically synthesized aglycones : (8S)-8-hydroxy-8-iodomethyloleandolide, 8-fluoromethyloleandolide, 9-bromooleandolide and 9-aminooleandolide were not. converted into the corresponding new antibiotics.
Although the development of mutants having lower substance-specificity is the coming problem, the present bioorganic approach is obviously the excellent method to clarify the biosynthesis of antibiotics.