Synthesis, membrane dynamics, and iron acquisition of structurally diverse siderophore amphiphiles

Amphiphilic siderophore are a class of less-well characterized bacterial iron chelators. Their unique structural motifs with hydrophilic iron-chelating moieties and hydrophobic chains make these amphiphiles both efficiently acquire iron and preferentially interact with membranes. However, little is known about how iron acquisition and membrane interactions of these amphiphiles are correlated with each other for bacterial uptake.; In Chapter 2 and Chapter 3, general methods are reported for the ready syntheses of the citrate-based siderophore amphiphiles acinetoferrin ( Af), rhizobactin-1021 (Rz) and their analogs via common precursors, amidated-tert-butyl-protected citrate intermediates. The 3-D structures of Af and Rz metal complexes were also investigated by 1H NMR and by Hartree-Fock ab initio and density functional theory (DFT) calculations. The structures indicate that Fe-Af and Fe-Rz should rapidly partition into and translocate through membranes.; Chapter 4 and Chapter 5 describe our studies about membrane dynamics of Af, Rz, saturated Af (Saf), mycobactin J ( MJ) and their metal complexes. All the iron-free amphiphiles have predictable membrane affinites (classic hydrophobic effect). In contrast, their iron complexes show diverse membrane-diffusion properties. The membrane affinities decrease >20-fold for Af and Saf upon iron chelation, in contrast to no change for Rz. Fe-MJ also shows preferential affinity for macrophage lipid-droplets vs macrophage or bacterial membranes. All the observations are explained well by the structures of the individual siderophore amphiphiles.; Iron acquisition properties of Af, Rz, and their analogs were investigated (Chapter 6 and Chapter 7). These amphiphiles rapidly mobilize iron from iron-citrate, transferrin and ferritin. Either hydroxamate-conjugated double bonds or the appended hydrophobic chains facilitate the iron acquisition from these biologically-relevant iron sources.; Chapter 8 reveals a novel mycobactin-mediated iron acquisition within macrophages. Readily membrane-diffusible MJ extracts macrophage-intracellular iron efficiently. Fe-MJ then selectively traffics to phagosome-adjacent, macrophage lipid-droplets for iron delivery to phagosomal mycobacteria.; All these results strongly argue that the structures of siderophore amphiphiles have been tuned to allow adaptation to various iron-restricted circumstances. These studies are not only beneficial for understanding amphiphile-mediated bacterial iron transport but also applicable to designing siderophore-based antibiotics and iron scavengers.