Novel and essential metallophores from multidrug resistant bacterial pathogens

项目总结/摘要 冠瘿碱金属载体是近年来发现的一种新型金属捕获小分子，由多种细菌产生 病原体：金黄色葡萄球菌、铜绿假单胞菌和鼠疫耶尔森菌。操纵子 生物合成、输出和再摄取仅在过去两年中报道，然而这些系统 已经显示出与菌血症、肺部感染和烧伤的小鼠模型的发病机制有关 伤口感染这些金属载体的生物合成特别有趣，因为它们不是由 通过研究充分的非核糖体肽合成酶或聚酮酶。相反，这些病原体 进化出依赖于烟酰胺合酶和冠瘿碱脱氢酶的生物合成系统。 烟酰胺转移酶（NAS）主要在植物中进行研究，并迭代地连接氨基丁酸酯， S-腺苷甲硫氨酸的部分。冠瘿螨酶（ODH）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。这两类酶都没有得到充分研究， 我们建议在这里填补这一空白的知识，提供一个结构生物学和机制酶学 这些酶的特性。我们还将提供第一个金属载体的结构表征 自己这一基础科学研究将为未来新型抗菌药物的开发奠定必要的基础 设计努力。

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.