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Antifungal Siderophore Conjugates for Theranostic Applications in Invasive Pulmonary Aspergillosis Using
Joachim Pfister1, Milos Petrik2, Katerina Bendova2
1Department of Nuclear Medicine, Medical University Innsbruck, A-6020 Innsbruck, Austria.
Abstract:
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 and existing antifungals can be constrained by dose-limiting toxicity and drug interaction. In this study, we modified triacetylfusarinine C (TAFC), the main siderophore produced by the opportunistic pathogen Aspergillus fumigatus (A. fumigatus), with antifungal molecules to perform antifungal susceptibility tests and molecular imaging. A variation of small organic molecules (eflornithine, fludioxonil, thiomersal, fluoroorotic acid (FOA), cyanine 5 (Cy5) with antifungal activity were coupled to diacetylfusarinine C (DAFC), resulting in a "Trojan horse" to deliver antifungal compounds specifically into A. fumigatus hyphae by the major facilitator transporter MirB. Radioactive labeling with gallium-68 allowed us to perform in vitro characterization (distribution coefficient, stability, uptake assay) as well as biodistribution experiments and PET/CT imaging in an IPA rat infection model. Compounds chelated with stable gallium were used for antifungal susceptibility tests. [Ga]DAFC-fludioxonil, -FOA, and -Cy5 revealed a MirB-dependent active uptake with fungal growth inhibition at 16 µg/mL after 24 h. Visualization of an A. fumigatus infection in lungs of a rat was possible with gallium-68-labeled compounds using PET/CT. Heterogeneous biodistribution patterns revealed the immense influence of the antifungal moiety conjugated to DAFC. Overall, novel antifungal siderophore conjugates with promising fungal growth inhibition and the possibility to perform PET imaging combine both therapeutic and diagnostic potential in a theranostic compound for IPA caused by A. fumigatus.
Insights
Researchers developed novel "Trojan horse" antifungal siderophore conjugates to target Aspergillus fumigatus infections. These compounds show promise for both inhibiting fungal growth and enabling diagnostic imaging in invasive pulmonary aspergillosis (IPA).
Area of Science:
- Mycology
- Medical Imaging
- Medicinal Chemistry
Background:
- Invasive pulmonary aspergillosis (IPA) poses a severe threat to immunocompromised individuals, with high mortality rates.
- Current diagnostic methods for IPA are often invasive or time-consuming, and existing antifungal treatments face challenges with toxicity and drug interactions.
- Triacetylfusarinine C (TAFC), a siderophore from Aspergillus fumigatus, can be modified to deliver antifungal agents.
Purpose of the Study:
- To synthesize and evaluate novel antifungal siderophore conjugates for targeted delivery of antifungal agents to Aspergillus fumigatus.
- To assess the antifungal activity and diagnostic potential of these modified siderophores using in vitro and in vivo models.
- To explore the theranostic capabilities of these conjugates for invasive pulmonary aspergillosis.
Main Methods:
- Modification of diacetylfusarinine C (DAFC) with various antifungal molecules (eflornithine, fludioxonil, thiomersal, fluoroorotic acid (FOA), cyanine 5 (Cy5)).
- Radioactive labeling with Gallium-68 for in vitro characterization and in vivo Positron Emission Tomography/Computed Tomography (PET/CT) imaging.
- Antifungal susceptibility testing and evaluation in an IPA rat infection model.
Main Results:
- Gallium-68-labeled DAFC conjugates ([Ga]DAFC-fludioxonil, -FOA, -Cy5) demonstrated MirB-dependent uptake and significant fungal growth inhibition (16 µg/mL after 24 h).
- Successful visualization of Aspergillus fumigatus infection in rat lungs using PET/CT imaging.
- Biodistribution patterns highlighted the impact of the conjugated antifungal moiety on compound behavior.
Conclusions:
- Novel antifungal siderophore conjugates exhibit potent antifungal activity and theranostic potential for IPA.
- These conjugates offer a targeted approach to combat Aspergillus fumigatus infections, combining therapeutic and diagnostic capabilities.
- The developed theranostic compounds could improve management of invasive pulmonary aspergillosis in at-risk patients.
