Journal
ACS INFECTIOUS DISEASES
Volume 8, Issue 9, Pages 1815-1822Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.2c001641815
Keywords
cationic amphiphiles; membrane disruption; antifungal drugs; steroids; imidazolium salts
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Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [SFB 858]
- ADAMA Center for Novel Delivery Systems in Crop Protection, Tel Aviv University
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A library of cationic, steroid-based imidazolium amphiphiles with tunable antifungal activity was reported. The adoption of an ergosterol-derived backbone increased the antifungal activity and selectivity, offering a promising platform for the development of improved amphiphilic fungicides.
Cationic amphiphiles have been reported to show broad antimicrobial activity. The potential for antimicrobial resistance to these molecules is low owing to their general cell membrane permeabilizing mode of action. However, their applications are often limited by toxicity resulting from their low selectivity for microbial cell membranes. Herein, we report a library of cationic, steroid-based imidazolium amphiphiles that show tunable antifungal activity in a variety of fungal pathogens of the genus Candida. We show that adoption of an ergosterol-derived backbone increases antifungal activity while modestly affecting hemolytic activity, thereby increasing overall selectivity by more than 8-fold in comparison to cholesterol-derived imidazolium salts. We hypothesize that this effect is caused by a privileged integration of the ergosterol-derived salts into fungal membranes leading to increased membrane disorder. We propose that these findings offer a useful platform for the development of improved amphiphilic fungicides.
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