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PEPTIDE AND PEPTIDE/NUCLEOSIDE ANTIBIOTICS

肽和肽/核苷抗生素

基本信息

批准号：
2459353
负责人：
T. MARK ZABRISKIE
金额：
$ 27.73万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-12-01 至 1999-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2459353
关键词：
Streptomyces antibiotics bacterial genetics biological products chemical structure function drug design /synthesis /production enzyme inhibitors enzyme mechanism mass spectrometry microorganism metabolism molecular cloning nuclear magnetic resonance spectroscopy nucleoside analog peptide analog

项目摘要

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.

该研究计划的广泛目标是了解哪些自然界中的化学反应以及它们之间的联系共同制造出具有重大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将合成、生物合成、酶学和分子学相结合的方法遗传学。这种跨学科的方法已经变得越来越多对于渴望研究的现代生物有机化学家来说是必不可少的新陈代谢、新陈代谢的调节及其后果。它就是这样的实验室的新化学家对生物学和解决重要生化问题的广泛技能正在被制作。这个项目的具体目标是继续开展S的杀虫工作，链霉素F和卷曲霉素1A。早些时候进行的研究美国国立卫生研究院支持的这一计划的各个阶段已经建立了重要的生物遗传学以及三者之间的生化联系，每一个都代表着一个大量的抗生素家族。研究设计包括结构设计研究确定每条途径中的生物合成中间体。这将是通过在体内使用酶抑制剂来阻断特定的生物合成步骤和诱导途径中间产物的积累，以及已经在杀菌方面取得了非常成功的方法路径。研究设计还将包括生化研究，以检测和表征催化许多重要的每条途径中的反应，并将包括克隆和几组酶的自抗性基因和生物合成基因的测序对相似或相同的反应进行相同或相似的反应，底物。新的核苷将从杀菌素和链霉菌素研究可能被证明直接有用，因为-或在设计 -抗病毒药物。卷曲霉素的研究可能提供新的线索抗分枝杆菌新“杀手”菌株的有效药物肺结核。