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

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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.