PEPTIDE AND PEPTIDE/NUCLEOSIDE ANTIBIOTICS

这项研究计划的主要目标是了解 自然界中的化学反应以及它们之间的联系 共同产生具有重要生物医学意义的复杂结构 相关活动。这一目标将通过多方面的 融合了合成、生物合成、酶学和分子生物学的方法 遗传学这种跨学科的方法已经越来越多 对于现代生物有机化学家来说， 代谢，其调节及其后果。正是在这样 实验室，新的化学家与生物学的理解和 解决重要生物化学问题的广泛技能正在被 制作。 该计划的具体目标是继续研究杀稻瘟菌素S， 链丝菌素F和卷曲霉素1A。在早期进行的研究 这个NIH支持的项目的各个阶段已经建立了重要的生物遗传学基础， 以及三者之间的生物化学联系，每一种都代表着 抗生素的大家族研究设计包括结构 研究，以确定在每个途径的生物合成中间体。这将 通过在体内使用酶抑制剂来阻断特异性的 生物合成步骤，并诱导途径中间体的积累， 已经非常成功的方法， 通路研究设计还将包括生化研究， 检测和表征催化许多重要的 反应，并将包括基因研究，以克隆和 对酶组的自身抗性基因和生物合成基因进行测序 对相似的，或相同的， 印刷受体. 将从杀稻瘟菌素中鉴定出的新核苷， 链丝菌素的研究可能证明是有用的直接作为-或在设计 - 抗病毒剂。卷曲霉素的研究可能会提供新的线索， 对抗分枝杆菌新“杀手”菌株的有效药物 结核

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.