TY - JOUR
T1 - New Application of Neomycin B-Bisbenzimidazole Hybrids as Antifungal Agents
AU - Thamban Chandrika, Nishad
AU - Shrestha, Sanjib K.
AU - Ranjan, Nihar
AU - Sharma, Anindra
AU - Arya, Dev P.
AU - Garneau-Tsodikova, Sylvie
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2018/2/9
Y1 - 2018/2/9
N2 - 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.
AB - 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.
KW - benzimidazoles
KW - biofilm
KW - cytotoxicity
KW - ergosterol
KW - hemolysis
KW - reactive oxygen species (ROS)
KW - time-kill
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UR - http://www.scopus.com/inward/citedby.url?scp=85041528958&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.7b00254
DO - 10.1021/acsinfecdis.7b00254
M3 - Article
C2 - 29227087
AN - SCOPUS:85041528958
VL - 4
SP - 196
EP - 207
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 2
ER -