Antifungal Siderophore Conjugates for Theranostic Applications in Invasive Pulmonary Aspergillosis Using Low-Molecular TAFC Scaffolds

Invasive pulmonary aspergillosis (IPA) is a life-threatening form of fungal infection, primarily in immunocompromised patients and associated with significant mortality. Diagnostic procedures are often invasive and/or time consuming existing antifungals can be constrained by dose-limiting toxicity drug interaction. In this study, we modified triacetylfusarinine C (TAFC), the main siderophore produced opportunistic pathogen Aspergillus fumigatus (A. fumigatus), antifungal molecules to perform susceptibility tests molecular imaging. A variation small organic (eflornithine, fludioxonil, thiomersal, fluoroorotic acid (FOA), cyanine 5 (Cy5) activity were coupled diacetylfusarinine (DAFC), resulting “Trojan horse” deliver compounds specifically into A. hyphae major facilitator transporter MirB. Radioactive labeling gallium-68 allowed us vitro characterization (distribution coefficient, stability, uptake assay) as well biodistribution experiments PET/CT imaging an IPA rat infection model. Compounds chelated stable gallium used for tests. [Ga]DAFC-fludioxonil, -FOA, -Cy5 revealed MirB-dependent active growth inhibition at 16 µg/mL after 24 h. Visualization lungs was possible gallium-68-labeled using PET/CT. Heterogeneous patterns immense influence moiety conjugated DAFC. Overall, novel conjugates promising possibility PET combine both therapeutic diagnostic potential theranostic compound caused fumigatus.