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Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy
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 mo...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087349/ https://www.ncbi.nlm.nih.gov/pubmed/35558105 http://dx.doi.org/10.3389/fmicb.2022.866840 |
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author | Augostine, Catheryn R. Avery, Simon V. |
author_facet | Augostine, Catheryn R. Avery, Simon V. |
author_sort | Augostine, Catheryn R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9087349 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90873492022-05-11 Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy Augostine, Catheryn R. Avery, Simon V. Front Microbiol 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. Frontiers Media S.A. 2022-04-26 /pmc/articles/PMC9087349/ /pubmed/35558105 http://dx.doi.org/10.3389/fmicb.2022.866840 Text en Copyright © 2022 Augostine and Avery. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Augostine, Catheryn R. Avery, Simon V. Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy |
title | Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy |
title_full | Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy |
title_fullStr | Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy |
title_full_unstemmed | Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy |
title_short | Discovery of Natural Products With Antifungal Potential Through Combinatorial Synergy |
title_sort | discovery of natural products with antifungal potential through combinatorial synergy |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087349/ https://www.ncbi.nlm.nih.gov/pubmed/35558105 http://dx.doi.org/10.3389/fmicb.2022.866840 |
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