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. Uptak...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2024-07, Vol.67 (14), p.12143-12154
Main Authors: Mular, Andrzej, Hubmann, Isabella, Petrik, Milos, Bendova, Katerina, Neuzilova, Barbora, Aguiar, Mario, Caballero, Patricia, Shanzer, Abraham, Kozłowski, Henryk, Haas, Hubertus, Decristoforo, Clemens, Gumienna-Kontecka, Elzbieta
Format: Article
Language:English
Subjects:
Animals
Aspergillosis - diagnostic imaging
Aspergillosis - microbiology
Aspergillus fumigatus - chemistry
Aspergillus fumigatus - metabolism
Biomimetic Materials - chemistry
Biomimetic Materials - metabolism
Deferoxamine - chemistry
Ferric Compounds - chemistry
Gallium Radioisotopes - chemistry
Mice
Peptides, Cyclic
Positron-Emission Tomography - methods
Siderophores - chemistry
Siderophores - metabolism
Species Specificity
Staphylococcus aureus - metabolism
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Summary: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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c00887