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The prevalence of drug-resistant pathogenic fungi is a major global health challenge. There is an urgent need for novel drugs that can exert a potent antifungal activity and overcome resistance. Newly discovered anti-fungal properties of existing compounds can potentially offer a rapid solution to address this persistent threat. We rationalized that structures which disrupt the fungal cell membrane could address the above unmet need. As fatty acids underpin the formation and stability of cell membranes, we used computational simulations to evaluate the interactions between selected short chain fatty acids and a model cell membrane. Here, we report that caprylic acid could penetrate and perturb the membrane  in silico . Based on the  in silico  findings, we identified a derivative of this fatty acid that disrupts fungal membranes as detected using steady-state fluorescence anisotropy. We show that this fatty acid derivative is potent against a variety of fungal pathogens like  Candida  and  Trichophyton . We further demonstrated the ability of this fatty acid derivative to potentiate some azoles  in vitro  and enhance the efficacy of antifungal formulations  in vivo.  Our data suggests the emergence of a novel therapy for effective disease management and overcoming anti-fungal drug resistance.

Mechanistic Insight Into the Antifungal Effects of a Fatty Acid Derivative Against Drug-Resistant Fungal Infections