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Biosynthesis of antifungal nucleoside antibiotics

抗真菌核苷抗生素的生物合成

基本信息

批准号：
10470406
负责人：
Kenichi Yokoyama
金额：
$ 33.97万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470406
关键词：
Acids Amides Anabolism Antibiotics Antifungal Agents Bacteria Carbohydrates Cell Wall Cellular Structures Chemicals Chitin Clinical Communicable Diseases Data Development Drug resistance Engineering Enzymatic Biochemistry Enzymes Excision Exhibits Foundations Funding Fungal Components Future Gene Cluster Gene Combinations Generations Genetic Genome Genomics Goals Growth Human Immunocompromised Host Knowledge Ligase Ligation Mediating Mining Mycoses Natural Products Nucleosides Oxygenases Pathway interactions Phosphorylation Phosphotransferases Physiological Polysaccharides Preparation Protein Dephosphorylation Public Health Reaction Reporting Research Resistance Specificity Streptomyces Structure Structure-Activity Relationship Substrate Specificity Testing Toxic effect Travel alpha ketoglutarate analog base carbohydrate structure clinical development combat desert fever experimental study fungus guided inquiry in vivo inorganic phosphate nikkomycin novel novel therapeutics nucleoside analog nucleoside triphosphatase pathogenic fungus reconstitution sugar text searching

项目摘要

Project Summary/Abstract Peptidyl nucleosides (PNs) are naturally occurring antifungal agents active against multiple pathogenic fungi such as the causal agent of “Valley Fever”. They also exhibit potent synergistic effects with clinically approved antifungal drugs. Our long-term goal is to provide a comprehensive understanding of both the biosynthesis of PNs and their mode of action. The current application focuses on the biosynthesis of PNs. Understanding PN biosynthetic pathways will provide a basis for creating structurally diverse PN analogs through engineered biosynthesis, semi synthesis and genome mining. In the previous funding cycle, we found that PNs are biosynthesized through cryptic phosphorylation and carbohydrate tailoring by oxidative C-C bond cleavage. On the basis of these findings, in this application, we will perform functional and mechanistic characterization of the biosynthetic enzymes to provide the foundation for genome mining discovery of novel nucleoside natural products and chemoenzymatic synthesis of unnatural PNs. In Aim 1, the mechanism of removal of cryptic phosphorylation and the generality of cryptic phosphorylation in other nucleoside biosynthesis pathways will be investigated. In Aim 2, the radical mediated divergent biosynthesis of nucleoside natural products will be investigated by studying the mechanism of oxidative C-C bond cleavage and genome mining characterization of homologous enzymes. In Aim 3, the mechanism of amide ligation by NikS/PolG enzymes will be characterized, and their potentials for use in the chemoenzymatic preparation of PNs will be investigated. The proposed research is significant because it will provide a basis for the future biosynthetic and chemoenzymatic generation of novel therapeutic PNs as well as genome mining discovery of novel antifungal nucleoside natural products.

项目摘要/摘要多肽核苷(PNS)是一种天然存在的抗真菌药物，对多种病原真菌具有活性。比如“谷热”的致病因素。它们还表现出强大的协同作用，与临床批准的抗真菌药物。我们的长期目标是提供对生物合成的全面了解 PNS及其行动模式。目前的应用重点是三七总皂苷的生物合成。了解PN 生物合成途径将为通过工程方法创造结构多样化的PN类似物提供基础生物合成、半合成和基因组挖掘。在前一个资金周期中，我们发现PNS是通过隐蔽的磷酸化合成，碳水化合物通过氧化C-C键断裂进行剪裁。在……上面在这些发现的基础上，在本应用程序中，我们将对生物合成酶为基因组挖掘发现新的天然核苷奠定基础非天然三七总皂苷的合成及化学酶促合成。在目标1中，去除隐语的机制其他核苷生物合成途径中的磷酸化和隐蔽磷酸化的共性将是调查过了。在目标2中，自由基介导的核苷天然产物的发散生物合成将是通过研究氧化C-C键断裂的机制和基因组挖掘特征进行了研究同源酶。在目标3中，将表征NIKS/Polg酶连接酰胺的机制，并对其在化学酶法制备三七总皂苷中的应用前景进行了研究。建议数这项研究具有重要意义，因为它将为未来的生物合成和化学酶生成提供基础新的治疗性三七的发现以及新的抗真菌核苷天然产物的基因组挖掘发现。