Novel and essential metallophores from multidrug resistant bacterial pathogens

项目摘要/摘要 光学金属载体是新近发现的一种新型金属捕集小分子，由多种细菌组成 病原体：金黄色葡萄球菌、铜绿假单胞菌和鼠疫耶尔森氏菌。的操纵曲 生物合成、出口和再吸收只是在过去两年才有报道，但这些系统已经 已经被证明与菌血症、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耐人寻味，因为它们不是 被研究得很好的非核糖体多肽合成酶或聚酮合成酶。相反，这些病原体 进化出一种依赖于烟碱合成酶和阿片脱氢酶的生物合成系统。 烟草胺合成酶(NAS)已经在植物中进行了初步研究，并反复加入氨基丁酸酯 S的部分腺苷蛋氨酸。阿片脱氢酶(ODH)是由植物病原体和软体动物产生的， 并在氨基酸和α-酮酸之间产生连接。这两类酶都没有得到很好的研究，所以 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。 这些酶的特性。我们还将提供金属载体的第一个结构表征 他们自己。这一基础科学研究将为未来新型抗菌药物的研制奠定必要的基础 设计方面的努力。

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.