Biomimetic Analogues of the Desferrioxamine E Siderophore for PET Imaging of Invasive Aspergillosis: Targeting Properties and Species Specificity

The pathogenic fungus Aspergillus fumigatus utilizes a cyclic ferrioxamine E (FOXE) siderophore to acquire iron
from the host. Biomimetic FOXE analogues were labeled with gallium-68
for molecular imaging with PET. [68Ga]Ga(III)-FOXE analogues
were internalized in A. fumigatus cells
via Sit1. Uptake of [68Ga]Ga(III)-FOX 2–5, the most
structurally alike analogue to FOXE, was high by both A. fumigatus and bacterial Staphylococcus
aureus. However, altering the ring size provoked species-specific
uptake between these two microbes: ring size shortening by one methylene
unit (FOX 2–4) increased uptake by A. fumigatus compared to that by S. aureus, whereas
lengthening the ring (FOX 2–6 and 3–5) had the opposite
effect. These results were consistent both in vitro and in vivo, including PET imaging in infection
models. Overall, this study provided valuable structural insights
into the specificity of siderophore uptake and, for the first time,
opened up ways for selective targeting and imaging of microbial pathogens
by siderophore derivatization.