Abstract
Alkylated aminoglycosides and bisbenzimidazoles have previously been shown to individually display antifungal activity. Herein, we explore for the first time the antifungal activity (in liquid cultures and in biofilms) of ten alkylated aminoglycosides covalently linked to either mono-or bisbenzimidazoles. We also investigate their toxicity against mammalian cells, their hemolytic activity, and their potential mechanism(s) of action (inhibition of fungal ergosterol biosynthetic pathway and/or reactive oxygen species (ROS) production). Overall, many of our hybrids exhibited broad-spectrum antifungal activity. We also found them to be less cytotoxic to mammalian cells and less hemolytic than the FDA-Approved antifungal agents amphotericin B and voriconazole, respectively. Finally, we show with our best derivative (8) that the mechanism of action of our compounds is not the inhibition of ergosterol biosynthesis, but that it involves ROS production in yeast cells.
Original language | English |
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Pages (from-to) | 196-207 |
Number of pages | 12 |
Journal | ACS Infectious Diseases |
Volume | 4 |
Issue number | 2 |
DOIs | |
State | Published - Feb 9 2018 |
Bibliographical note
Funding Information:This work was supported by startup funds from the University of Kentucky (to S.G.-T.) and by NIH grants AI090048 (to S.G.-T.), GM097917 (to D.P.A.), and AI114114 (to D.P.A.).
Publisher Copyright:
© 2017 American Chemical Society.
Keywords
- benzimidazoles
- biofilm
- cytotoxicity
- ergosterol
- hemolysis
- reactive oxygen species (ROS)
- time-kill
ASJC Scopus subject areas
- Infectious Diseases