New application of neomycin B–bisbenzimidazole hybrids as antifungal agents

N Thamban Chandrika, SK Shrestha… - ACS infectious …, 2018 - ACS Publications
ACS infectious diseases, 2018ACS Publications
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 …
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.
ACS Publications
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