Abstract
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.
Highlights
The emergence of drug-resistant microbes is a major global challenge
We demonstrate in vitro synergistic action of propylene glycol monocaprylate (PGMC) and azole antifungals with improved in vitro efficacy of antifungal formulations containing PGMC against C. albicans and Trichophyton spp
Commensal fungi like certain Candida spp. that commonly reside on healthy skin (Findley et al, 2013), often increase in abundance and become pathogenic during host immunodeficiencies (Oh et al, 2013)
Summary
The emergence of drug-resistant microbes is a major global challenge. While the term “drugresistant microbes” is most commonly associated with antibiotic-resistant bacteria, the Centers for Disease Control and Prevention (CDC) has recently highlighted drug-resistant fungal infections as an emerging threat. The limited arsenal of antifungal agents and the paucity of novel antifungal agents in the pipeline exposes a serious vulnerability in our preparation to deal with this existing challenge, concerns about which were raised almost two decades ago (Sanglard and Odds, 2002). Previous studies have reported both pro-growth and inhibitory activity of fatty acids against microbes (Nieman, 1954; Desbois and Smith, 2010; Pohl et al, 2011). Jadhav et al (2017), demonstrated that capric and caprylic acids inhibit processes involved in Candida albicans virulence like morphogenesis, adhesion and biofilm formation Their primary mode of antifungal action is through membrane perturbations in the target organism (Pohl et al, 2011). A scientific understanding of these behaviors could enable the repositioning of fatty acids and/or their derivatives as novel treatments or potentiators of known antifungals against drug-resistant fungi
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