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

在化学部生命过程化学项目的支持下，加州大学圣巴巴拉分校的艾莉森·巴特勒博士将研究细菌产生的称为铁载体的化合物，以获得铁，铁是大多数细菌生长所必需的营养物质。铁载体在希腊语中的意思是喜欢铁(Sideros)(Phore)，它以非常高的亲和力结合铁并将其运输到细菌的细胞中，这是细菌生命所必需的过程。巴特勒博士和她的团队将专注于手性对细菌吸收铁的影响的研究，即手性的左手或右手形状。如果手性可以被用来干扰微生物吸收铁的过程，从这项研究中获得的新知识可能有助于控制有害的微生物感染。参与研究的研究生和本科生将获得生物无机化学和生物有机化学方面的广泛教育和培训，以及跨学科研究的基础，这可能对他们未来的职业生涯有用。她和她的学生还将通过加州大学伯克利分校的科学与工程合作中心和科学与数学暑期研究所(SIMS)开展外展工作坊，以帮助本科生发展有效的科学交流技能，并帮助导师制定有效的指导策略。该奖项支持的研究重点是一种新的三儿茶酚铁载体组合套件，三-(2，3-二HB-L/D-CAA-L-Ser)，其中DHB IF二羟基苯甲酸酯和CAA是阳离子氨基酸L/D-赖氨酸，L/D-精氨酸或L/D-Orn。每个铁载体的非对映异构体对与Fe(III)形成对映体的络合物。本研究的具体目的是(I)阐明控制Fe(III)-对映体配合物手性的结构和分子特征；(Ii)研究Fe(III)在非对映异构体铁载体之间的交换，包括CAA的性质对交换过程的影响；以及3)研究Fe(III)-[Tris(2，3-DHB-L/D-CAA-L-Ser)]的立体化学对微生物生长的影响。新的铁载体将被分离，相关的合成类似物将被合成，并将对两者进行结构表征。将对Fe(III)-铁载体配合物和适当的合成类似物进行圆二色谱、外消旋晶化和分子模拟。Fe(III)的交换动力学将遵循圆二色谱。该奖项反映了NSF的法定使命，通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为是值得支持的。

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.