Prodrugging fungicidal amphotericin B significantly decreases its toxic effects
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
39673865
DOI
10.1016/j.ejmech.2024.117157
PII: S0223-5234(24)01039-0
Knihovny.cz E-zdroje
- Klíčová slova
- Amphotericin, Antifungal, Aspergillus fumigatus, Candida albicans, Fungal infection, Galleria mellonella, Prodrugs, Toxicity,
- MeSH
- amfotericin B * farmakologie MeSH
- antifungální látky * farmakologie chemie chemická syntéza MeSH
- Aspergillus účinky léků MeSH
- Candida účinky léků MeSH
- larva účinky léků MeSH
- mikrobiální testy citlivosti * MeSH
- molekulární struktura MeSH
- můry účinky léků MeSH
- prekurzory léčiv * farmakologie chemie chemická syntéza MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- amfotericin B * MeSH
- antifungální látky * MeSH
- prekurzory léčiv * MeSH
Amphotericin B (AmB) is one of the most effective antifungal drugs, with a strong, dose-dependent activity against most Candida and Aspergillus species responsible for life-threatening infections. However, AmB is severely toxic, which hinders its broad use. In this proof-of-concept study, we demonstrate that prodrugging AmB considerably decreases AmB toxicity without affecting its fungicidal activity. For this purpose, we modified the AmB structure by attaching a designer phosphate promoiety, thereby switching off its mode of action and preventing its toxic effects. The original fungicidal activity of AmB was then restored upon prodrug activation by host plasma enzymes. These AmB prodrugs showed a safer toxicity profile than commercial AmB deoxycholate in Candida and Aspergillus species and significantly prolonged larval survival of infected Galleria mellonella larvae. Based on these findings, prodrugging toxic antifungals may be a viable strategy for broadening the antifungal arsenal, opening up opportunities for targeted prodrug design.
Citace poskytuje Crossref.org
