PEPTIDE AND PEPTIDE/NUCLEOSIDE ANTIBIOTICS

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The broad objective of this research program is to understand which chemical reactions are available in Nature and how they are linked together to produce complex structures with significant bio-medically relevant activity. This objective will be attained through a multi-faceted approach that blends synthesis, biosynthesis, enzymology and molecular genetics. Such an interdisciplinary approach has become more and more essential for the modern bioorganic chemist who desires to study metabolism, its regulation and its consequences. It is in such laboratories that new chemists with an understanding of biology and a broad range of skills for solving important biochemical problems are being produced. The specific aims of this program are to continue work on blasticidin S, streptothricin F and capreomycin 1A. Research carried out during earlier phases of this NIH supported program has established important biogenetic and biochemical connections amongst the three, and each represents a substantial family of antibiotics. The Research Design includes structural studies to identify biosynthetic intermediates in each pathway. This will be done through the in vivo use of enzyme inhibitors to block specific biosynthetic steps and induce accumulation of pathway intermediates, an approach that has already been very successful with the blasticidin pathway. The Research Design will also include biochemical studies to detect and characterize enzymes that catalyze a number of important reactions in each pathway, and will include genetIcs studies to clone and sequence self-resistance genes and biosynthetic genes for sets of enzymes that carry out the same, or similar, reaction on similar, or identical, substrates. New nucleosides that will be identified from the blasticidin and streptothricin studies may prove useful directly as - or in the design of - antiviral agents. The capreomycin studies may provide new leads to efficacious agents against the new "killer" strains of Mycobacterium tuberculosis.