Prodrugging fungicidal amphotericin B significantly decreases its toxic effects.

Eur J Med Chem

Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, Prague, 128 00, Czech Republic; Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo Nám. 542/2, Prague, 160 00, Czech Republic. Electronic address:

Published: December 2024

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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2024.117157DOI Listing

Publication Analysis

Top Keywords

toxic effects
8
amb
8
candida aspergillus
8
aspergillus species
8
fungicidal activity
8
prodrugging fungicidal
4
fungicidal amphotericin
4
amphotericin decreases
4
toxic
4
decreases toxic
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!