Novel Teicoplanins by Directed Biosynthesis.

The Journal of Antibiotics
1997.0

Abstract

Teicoplanin, a clinically useful glycopeptide antibiotic, is produced by Actinoplanes teichomyceticus as a complex of five main components, denoted factors A2-1 to A2-5, differing in the structure of their acyl side chain, which is linear in A2-1 and A2-3 and branched in the other components. In a previous paper it was shown that the acyl moieties of the teicoplanin complex originate from stepwise shortening, through the usual β oxidation mechanism, of long chain fatty acids constituting the membrane of A. teichomyceticus cells. In fact there is a clear correspondence between the relative amount of a given fatty acid in the cell membrane and the amount of the teicoplanin component having as side chain the structurally related branched or linear acid. For instance, the amount of component A2-3, characterized by a linear C10:0 acyl chain, depends on the amount of oleic acid, whereas the production of A2-1, characterized by a linear C10:1 acyl moiety, is entirely dependent on the addition of linoleate to the medium. This suggested the possibility of obtaining new members of the teicoplanin family by feeding A. teichomyceticus cultures with different eighteen carbons fatty acids having specific structural features. Our assumption was that these acids would be shortened (starting from the carboxyl group) to the proper length, i.e. ten carbons, and condensed to the core molecule. Therefore, it could be predicted that addition of linolenic acid (which is a linear eighteen carbon chain bearing double bonds in the 9th, 12th and 15th positions) would give a teicoplanin having an acyl moiety characterized by two double bonds in the 4th and 7th positions, and that ricinoleic acid (which is a linear eighteen carbon chain bearing a double bond in the 9th position and a hydroxy group in the 12th position) would give a teicoplanin having an acyl moiety characterized by a hydroxyl in the 4th position. The preparation and physico-chemical characterization of these two novel teicoplanins bearing a 4,7-decadienoic acyl moiety (I) and a 4-hydroxy-decanoic acyl moiety (II) are reported hereby.

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