Artificial SiderophoreModification and Metal CoordinationProviding Selectivity for Imaging of Bacterial Infections

Abstract Purpose: diagnosing bacterial infections can be challenging, as the source of infection is often difficult to identify. Positron emission tomography (PET) imaging with bacteria-specific agents offers a promising approach to localizing and potentially characterizing infection sites. In this study, we compared the selectivity of two iron chelators, the natural siderophore FOX E and its synthetic variant FOX 2–5, for targeting different pathogens when radiolabeled for molecular imaging. Methods: Both siderophores were evaluated across various bacteria, including Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Staphylococcus aureus, and Escherichia coli. The siderophores were labeled with radioactive gallium-68 and iron-59 for short-term uptake assays. In addition, 68Ga-labeled siderophores were applied in a murine infection model of the respective pathogens for PET imaging. Results: Our in vitro results demonstrated that both siderophores were taken up by bacteria when labeled with iron-59. However, when labeled with gallium-68, FOX 2–5 exhibited strain-specific differences: while gallium-68 uptake was similar for both chelators in S. aureus and A. baumannii, FOX 2–5 failed to accumulate in P. aeruginosa and K. pneumoniae unlike FOX E. These findings were confirmed in vivo with corresponding differences in the PET images of mouse infection models. Conclusion: minor modifications in the structure of siderophores can alter bacterial specificity, particularly when coordinated with gallium. Additionally, this study revealed a distinction in recognition between gallium and iron complexes in the Gram-negative P. aeruginosa and K. pneumoniae. These findings highlight artificial siderophores as versatile, customizable agents for characterizing and potentially diagnosing bacterial infections.