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Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy

Augostine, Catheryn R.; Avery, Simon V.

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Catheryn R. Augostine

Professor of Eukaryotic Microbiology


The growing prevalence of antifungal drug resistance coupled with the slow development of new, acceptable drugs and fungicides has raised interest in natural products (NPs) for their therapeutic potential and level of acceptability. However, a number of well-studied NPs are considered promiscuous molecules. In this study, the advantages of drug–drug synergy were exploited for the discovery of pairwise NP combinations with potentiated antifungal activity and, potentially, increased target specificity. A rational approach informed by previously known mechanisms of action of selected NPs did not yield novel antifungal synergies. In contrast, a high-throughput screening approach with yeast revealed 34 potential synergies from 800 combinations of a diverse NP library with four selected NPs of interest (eugenol, EUG; β-escin, ESC; curcumin, CUR; berberine hydrochloride, BER). Dedicated assays validated the most promising synergies, namely, EUG + BER, CUR + sclareol, and BER + pterostilbene (PTE) [fractional inhibitory concentrations (FIC) indices ≤ 0.5 in all cases], reduced to as low as 35 (BER) and 7.9 mg L–1 (PTE). These three combinations synergistically inhibited a range of fungi, including human or crop pathogens Candida albicans, Aspergillus fumigatus, Zymoseptoria tritici, and Botrytis cinerea, with synergy also against azole-resistant isolates and biofilms. Further investigation indicated roles for mitochondrial membrane depolarization and reactive oxygen species (ROS) formation in the synergistic mechanism of EUG + BER action. This study establishes proof-of-principle for utilizing high-throughput screening of pairwise NP interactions as a tool to find novel antifungal synergies. Such NP synergies, with the potential also for improved specificity, may help in the management of fungal pathogens.


Augostine, C. R., & Avery, S. V. (2022). Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy. Frontiers in Microbiology, 13, Article 866840.

Journal Article Type Article
Acceptance Date Mar 23, 2022
Online Publication Date Apr 26, 2022
Publication Date Apr 26, 2022
Deposit Date Apr 1, 2022
Publicly Available Date Apr 26, 2022
Journal Frontiers in Microbiology
Electronic ISSN 1664-302X
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 13
Article Number 866840
Keywords Microbiology (medical); Microbiology
Public URL
Publisher URL


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