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.

Department of Nuclear Medicine Medical University Innsbruck A 6020 Innsbruck Austria

Department of Organic Chemistry The Weizmann Institute of Science Rehovot 7610001 Israel

Faculty of Chemistry University of Wrocław 50 383 Wrocław Poland

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry and Czech Advanced Technology and Research Institute Palacky University 77900 Olomouc Czech Republic

Institute of Molecular Biology Biocenter Medical University Innsbruck A 6020 Innsbruck Austria

Public Higher Medical Professional School in Opole Katowicka 68 45 060 Opole Poland

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