Abstract
Antifungal resistance of human fungal pathogens represents an increasing challenge in modern medicine. Short antimicrobial peptides (AMP) display a promising class of antifungals with a different mode of action, but lack target specificity and metabolic stability. In this study the hexapeptide PAF26 (Ac-dArg-dLys-dLys-dTrp-dPhe-dTrp-NH2) and the three amino acid long peptide NLF (H2N-Asn-Leu-dPhe-COOH) were coupled to diacetylfusarinine C (DAFC), a derivative of the siderophore triacetylfusarinine C (TAFC) of Aspergillus fumigatus, to achieve targeted delivery for treatment of invasive aspergillosis. Conjugated compounds in various modifications were labelled with radioactive gallium-68 to perform in vitro and in vivo characterizations. LogD, serum stability, uptake- growth promotion- and minimal inhibitory concentration assays were performed, as well as in vivo stability tests and biodistribution in BALB/c mice. Uptake and growth assays revealed specific internalization of the siderophore conjugates by A. fumigatus. They showed a high stability in human serum and also in the blood of BALB/c mice but metabolites in urine, probably due to degradation in the kidneys. Only PAF26 showed growth inhibition at 8 µg/ml which was lost after conjugation to DAFC. Despite their lacking antifungal activity conjugates based on a siderophore scaffold have a potential to provide the basis for a new class of antifungals, which allow the combination of imaging by using PET/CT with targeted treatment, thereby opening a theranostic approach for personalized therapy.
Highlights
The airborne fungus Aspergillus fumigatus (A. fumigatus) is responsible for local and systemic infectious diseases, especially in immunocompromised patients
Peptide synthesis and conjugation to the siderophore were achieved with high chemical purity (80–90% monitored by analytical RP-HPLC)
Radiolabelling with the modified siderophore was achieved within 10 min at room temperature, with quantitative radiochemical yields (>95%)
Summary
The airborne fungus Aspergillus fumigatus (A. fumigatus) is responsible for local and systemic infectious diseases, especially in immunocompromised patients. A major threat is invasive pulmonary aspergillosis (IPA), a systemic opportunistic infection of the lung with a mortality rate of up to 90%. The reasons for this high lethality rate origin from insufficient diagnostic methods, but even if IPA is diagnosed early, overall mortality of 50% occurs [1]. It is of high interest to develop new diagnostic as well as therapeutic options. A big challenge for A. fumigatus during the infection process represents the hostile environment in the host. One of the most important limiting factors of fungal development is iron supply. One of the most important limiting factors of fungal development is iron supply. [2] A
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