Bioinorganic Chemistry of Catechol-Amine Siderophores and Biomimetic Analogs: Chirality of Iron Coordination and Bacterial Uptake

儿茶酚胺铁载体和仿生类似物的生物无机化学：铁配位的手性和细菌摄取

• 批准号: 2108596
• 负责人: Alison Butler
• 金额: $ 50.4万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2108596&HistoricalAwards=false
• 关键词: Bioinorganic; Chemistry; Catechol; Amine; Siderophores

With the support of the Chemistry of Life Processes Program in the Chemistry Division, Dr. Alison Butler from the University of California-Santa Barbara will investigate compounds called siderophores that bacteria produce to obtain iron, an essential nutrient for the growth of most bacteria. Siderophores, which is Greek for iron (sideros)-liking (phore), bind iron with very high affinity and transport it into the cells of bacteria, which is a process essential for the life of the bacteria. Dr. Butler and her team will focus on the study of the effect of chirality, i.e. their left handed or right handed shape, on the iron uptake by the bacteria. The new knowledge gained from this study may be beneficial to the control of deleterious microbial infections if the chirality could be used to disrupt the process of iron uptake by microbes. The graduate and undergraduate students involved in the research will acquire a broad education and training in bioinorganic and bioorganic chemistry as well as a foundation in interdisciplinary research, likely to be useful in their future careers. The PI and her students will also engage in outreach workshops through UCSB’s Center for Science and Engineering Partnerships (CSEP) and the Summer Institute in Science and Math (SIMS) to assist undergraduates in developing effective scientific communication skills and to assist mentors in developing effective mentoring strategies.The research supported by this award focuses on a new combinatoric suite of tris-catechol siderophores, tris-(2,3-DHB--L/D-CAA--L-Ser), in which DHB if dihydroxybenzoate and CAA is the cationic amino acid L/D-Lys, L/D-Arg or L/D-Orn. The diastereomeric pairs of each siderophore form complexes with Fe(III), which are enantiomeric. The specific aims of the research are (i) to elucidate the structural and molecular characteristics that govern the chirality of the Fe(III)-enantiomeric complexes, (ii) to investigate the exchange of Fe(III) between diastereomeric siderophores, including the effect of the nature of the CAA on the exchange process; and 3) to investigate the influence of the stereochemistry of Fe(III)-[tris(2,3-DHB--L/D-CAA--L-Ser)] on microbial growth. The new siderophores will be isolated, relevant synthetic analogues will be synthesized and both will be structurally characterized. Circular dichroism, racemic crystallization, and molecular modeling will be carried out on the Fe(III)-siderophore complexes and appropriate synthetic analogues. The kinetics of Fe(III) exchange will be followed by circular dichroism. Microbial growth will be monitored in disk-diffusion bioassays.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学过程的化学过程中的支持下，加利福尼亚 - 圣塔芭芭拉分校的艾莉森·巴特勒（Alison Butler）博士将调查称为铁载体的化合物，这些化合物生产以获得铁，这是大多数细菌生长的必不可少的营养素。铁载体是铁（Sideros）的希腊语（phore），它具有非常高亲和力的铁并将其运输到细菌细胞中，这是细菌寿命必不可少的过程。巴特勒博士和她的团队将专注于研究手性影响的研究，即他们的左手或右手形状，对细菌的铁吸收。如果可以使用手性来破坏微生物的铁吸收过程，那么这项研究从这项研究中获得的新知识可能对控制精致的微生物感染有益。参与研究的研究生和本科生将获得生物无机和生物有机化学的广泛教育和培训，以及跨学科研究的基础，可能对他们未来的职业有用。 The PI and her students will also engage in outreach workshops through UCSB’s Center for Science and Engineering Partnerships (CSEP) and the Summer Institute in Science and Math (SIMS) to assist undergraduates in developing effective scientific communication skills and to assist mentors in developing effective mentoring strategies.The research Supported by this award focuses on a new combinatoric suite of tris-catechol siderophores, Tris-（2,3-DHB-L/D-CAA-L-SER），其中DHB如果二羟基苯甲酸酯和CAA是阳离子氨基酸L/D-LYS，L/D-ARG或L/D-orn。每个辅助载体的非对映体对形成映体的Fe（III）。该研究的具体目的是（i）阐明控制Fe（III） - 元素综合体的手性的结构和分子特征，（ii）研究了对非映体的siderophores之间的Fe（III），包括CAA性质对交换过程的影响； 3）研究Fe（III）立体化学的影响 - [TRIS（2,3-DHB-L/D-CAA-L-SER）]对微生物生长的影响。新的铁载体将被隔离，相关的合成类似物将被合成，并在结构上表征。 Fe（III） - 辅助载体复合物和适当的合成类似物将进行圆形二色性，外表面结晶和分子建模。 Fe（III）交换的动力学将随后进行圆形二色性。微生物生长将在磁盘扩散生物测定中进行监测。该奖项反映了NSF的法定任务，并通过使用基金会的知识分子优点和更广泛的影响评估标准来评估值得支持。

项目成果

Mining elements of siderophore chirality encoded in microbial genomes

挖掘微生物基因组中编码的铁载体手性元素

• DOI: 10.1002/1873-3468.14539
• 发表时间: 2023
• 期刊: FEBS Letters
• 影响因子: 3.5
• 作者: Butler, Alison;Jelowicki, Aneta M.;Ogasawara, Haley A.;Reitz, Zachary L.;Stow, Parker R.;Thomsen, Emil
• 通讯作者: Thomsen, Emil

Ruckerbactin Produced by Yersinia ruckeri YRB Is a Diastereomer of the Siderophore Trivanchrobactin Produced by Vibrio campbellii DS40M4

由鲁克氏耶尔森菌 YRB 产生的 Ruckerbactin 是由坎贝氏弧菌 DS40M4 产生的铁载体 Trivanchrobactin 的非对映异构体

• DOI: 10.1021/acs.jnatprod.1c01047
• 发表时间: 2021
• 期刊: Journal of Natural Products
• 影响因子: 5.1
• 作者: Thomsen, Emil;Reitz, Zachary L.;Stow, Parker R.;Dulaney, Kalana;Butler, Alison
• 通讯作者: Butler, Alison

Marine Microbial Siderophores: Reactivity and Structural Diversity

海洋微生物铁载体：反应性和结构多样性

• 发表时间: 2022
• 期刊: The chemist
• 作者: Alison Butler