Novel and essential metallophores from multidrug resistant bacterial pathogens

来自多重耐药细菌病原体的新型和必需的金属载体

基本信息

批准号：
10211388
负责人：
AUDREY L LAMB
金额：
$ 28.75万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10211388
关键词：
Amines Amino Acids Aminobutyric Acids Anabolism Antibiotic Resistance Attenuated Bacteremia Bacteria Basic Science Binding Biological Assay Bubonic Plague Carbon Cobalt Crystallization Dangerousness Distant Drug Design Endocarditis Enzymatic Biochemistry Enzymes Evolution Exhibits Foundations Future Generations Glutamates Goals Growth Histidine Human In Vitro Iron Keto Acids Kinetics Knowledge Life Ligase Link Literature Lung infections Metals Modeling Multi-Drug Resistance Names Nickel Nutritional Immunity Operon Oxidoreductase Pathogenesis Pathway interactions Physical condensation Plants Pneumonic Plague Population Pseudomonas aeruginosa Reporting Research S-Adenosylmethionine Scallop Schiff Bases Septicemic plague Siderophores Staphylococcus aureus Staphylococcus aureus infection Structure System Therapeutic Virulence Work Wound Infection Yersinia pestis aminobutyrate antibiotic resistant infections antimicrobial antimicrobial drug burn wound design in vivo metal chelator mortality mouse model mutant novel pathogen pathogenic bacteria peptide synthase polyketide synthase pyochelin pyoverdin response small molecule structural biology uptake ventilator-associated pneumonia yersiniabactin

项目摘要

Project Summary/Abstract Opine metallophores are recently identified novel metal acquisition small molecules made by diverse bacterial pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, and Yersinia pestis. The operons for biosynthesis, export and re-uptake have only been reported in the last two years, and yet these systems have already been shown to be linked to pathogenesis in mouse models for bacteremia, lung infections and burn wound infections. The biosynthesis of these metallophores is especially intriguing, because they are not made by the well-studied nonribosomal peptide synthetases or polyketide synthases. Instead, these pathogens have evolved a biosynthetic system that is dependent on a nicotianamine synthase and an opine dehydrogenase. Nicotianamine synthases (NAS) have been primarily studied in plants, and iteratively join the aminobutyrate moieties of S-adenosylmethionine. Opine dehydrogenases (ODH) are made by plant pathogens and molluscs, and generate linkages between an amino acid and an α-keto acid. Neither class of enzymes in well-studied, so we propose here fill to this gap-in-knowledge, providing a structural biology and mechanistic enzymology characterization of these enzymes. We will also provide the first structural characterization of the metallophores themselves. This basic science research will lay the necessary foundation for future novel antimicrobial drug design efforts.

项目概要/摘要 Opine 金属载体是最近发现的由多种细菌产生的新型金属采集小分子病原体：金黄色葡萄球菌、绿脓杆菌、鼠疫耶尔森菌。生物合成、输出和再摄取直到最近两年才被报道，但这些系统已经已被证明与小鼠菌血症、肺部感染和烧伤模型的发病机制有关这些金属载体的生物合成特别令人感兴趣，因为它们不是制造出来的。相反，这些病原体具有经过充分研究的非核糖体肽合成酶或聚酮化合物合成酶。进化出依赖于烟酰胺合成酶和鸦片脱氢酶的生物合成系统。烟胺合酶 (NAS) 主要在植物中进行研究，并反复加入氨基丁酸 S-腺苷甲硫氨酸部分由植物病原体和软体动物产生。并在氨基酸和 α-酮酸之间产生连接，这两类酶都没有经过充分研究。我们建议在这里填补这一知识空白，提供结构生物学和机械酶学我们还将提供金属团的第一个结构表征。这项基础科学研究将为未来新型抗菌药物奠定必要的基础。设计努力。