Metallophores as Tools for Antibiotic Drug Development and the Study of Bacterial Metal Homeostasis

Xenometallomycins are a new class of antibiotic drug molecules with great potential and yet unknown mechanisms of action. A better understanding of the uptake and mechanism of action of these compounds will inform the rational structural design of next generation xenometallomycins. This dissertation details the development of novel molecular tools to elucidate the stability and uptake mechanisms of xenometallophores and xenometallophore-siderophore antibiotic conjugates. These efforts include the development of a dual radiolabeling strategy utilizing ⁶⁷Ga and ¹²⁴I to investigate the in vivo and in vitro stability of xenometallophores; The design, synthesis, and validation of multimodal chemical tagging strategies for deferoxamine-based siderophore photoaffinity probes, incorporating a diazirine photoactive moiety, aimed to evaluate reactivity and labeling preferences in single amino acid residues and siderophore protein; and the application of these deferoxamine-diazirine probes in live cells for protein target labeling, visualization, and identification.