Biosynthesis and chemical synthesis of biologically active compounds--antibiotics of microbial origin and antiviral, antitumor or antimicrobial compounds from marine tunicates and sponges--will be studied. Special attention will be directed toward the biosynthesis of antibiotics containing a "m-C7N" unit--geldanamycin, streptovaricin, pactamycin, validamyin--with the goal of identifying intermediates between the known primary precursors and the intact antibiotics. We also plan to focus on intermediates involved in the biosynthesis of the aminocyclitol antibiotics neomycin and validamycin, as well as on the origins of unusual biosynthetic units found in the peptide antibiotics berninamycin and emerimicin and in the acyltetramic acid streptolydigin. These studies will employ precursors labeled with radioactive and stable isotopes and extensive applications of NMR spectroscopy. As an adjunct to the biosynthetic studies, we plan to use mutant strains of the producing organisms and chemically prepared mutasynthons (analogs of 6-methylsalicylic acid, m-aminobenzoic acid, deoxystreptamine and neamine, 3-amino-4,7-dihydroxycoumarin and 3-amino-5-hydroxybenzoic acid) to prepare new mutasynthetic antibiotics related to pactamycin, neomycin, novobiocin and, perhaps, geldanamycin. We also plan to stress biosynthetic efforts in the area of marine natural products, continuing our studies of bromotyrosine metabolites from the sponge Aplysina fistularis and investigating the biosyntheses of eudistomins, antiviral Beta-carbolines from the tunicate Eudistoma olivaceum; of didemmnins, antiviral, antitumor and immunosuppressive cyclic depsipeptides from the tunicate Trididemnum sp.; of ptilocaulin from the sponge Ptilocaulis gracilis; and of sceptrin from the sponge Agelas clathrodes. Finally, we plan to carry out chemical syntheses of the most biologically promising marine-derived compounds--the didemnins, the eudistomins, and their analogs.
NIH ExPorter
NIH ExPorter