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Novel combinations of agents targeting translation that synergistically inhibit fungal pathogens

Vallières, Cindy; Raulo, Roxane; Dickinson, Matthew; Avery, Simon V.

Authors

Cindy Vallières

Roxane Raulo

SIMON AVERY simon.avery@nottingham.ac.uk
Professor of Eukaryotic Microbiology



Abstract

A range of fungicides or antifungals are currently deployed to control fungi in agriculture or medicine, but resistance to current agents is growing so new approaches and molecular targets are urgently needed. Recently, different aminoglycoside antibiotics combined with particular transport inhibitors were found to produce strong, synergistic growth-inhibition of fungi, by synergistically increasing the error rate of mRNA translation. Here, focusing on translation fidelity as a novel target for combinatorial antifungal treatment, we tested the hypothesis that alternative combinations of agents known to affect the availability of functional amino acids would synergistically inhibit growth of major fungal pathogens. We screened 172 novel combinations against three phytopathogens (Rhizoctonia solani, Zymoseptoria tritici, Botrytis cinerea) and three human pathogens (Cryptococcus neoformans, Candida albicans, Aspergillus fumigatus), showing that 48 combinations synergistically inhibited growth. Of these, 23 combinations were effective against more than one pathogen, including combinations comprising food-and-drug approved compounds, e.g., quinine with bicarbonate, and quinine with hygromycin. These combinations (fractional inhibitory combination [FIC] index [less than] 0.5) gave up to 100% reduction of fungal growth yield at concentrations of agents which, individually, had negligible effect. No synergy was evident against bacterial, plant or mammalian cells, indicating specificity for fungi. Mode-of-action analyses for quinine + hygromycin indicated that synergistic mistranslation was the antifungal mechanism. That mechanism was not universal as bicarbonate exacerbated quinine action by increasing drug uptake. The study unveils chemical combinations and a target process with potential for control of diverse fungal pathogens, and suggests repurposing possibilities for several current therapeutics.

Citation

Vallières, C., Raulo, R., Dickinson, M., & Avery, S. V. (2018). Novel combinations of agents targeting translation that synergistically inhibit fungal pathogens. Frontiers in Microbiology, 9, https://doi.org/10.3389/fmicb.2018.02355

Journal Article Type Article
Acceptance Date Sep 14, 2018
Online Publication Date Oct 4, 2018
Publication Date Oct 4, 2018
Deposit Date Sep 18, 2018
Publicly Available Date Oct 4, 2018
Journal Frontiers in Microbiology
Electronic ISSN 1664-302X
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 9
Article Number 2355
DOI https://doi.org/10.3389/fmicb.2018.02355
Keywords Antifungal combinations; Amino acids; Synergistic fungicides; Plant pathogens; Fungal disease; Crop protection
Public URL https://nottingham-repository.worktribe.com/output/1080770
Publisher URL https://www.frontiersin.org/articles/10.3389/fmicb.2018.02355/

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/





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