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, and Botrytis cinerea) and three human pathogens (Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus), showing that 48 combinations inhibited strongly the growth of the pathogens; the growth inhibition effect was significantly greater with the agents combined than by a simple product of their individual effects at the same doses. 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 ≤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.
Highlights
A wide range of fungi are undesirable for different reasons, including human and plant pathogens
Pathogenic organisms used in this study were the yeasts C. albicans SC5314 and C. neoformans 1841, the filamentous fungi A. fumigatus CBS 144.89, Botrytis cinerea SAR109940, Rhizoctonia solani AG2-1 1939 and Zymoseptoria tritici, and the bacterium Pseudomonas aeruginosa PA-W1
The filamentous fungi were routinely maintained and grown on potato dextrose agar or broth [PDA (Oxoid) or PDB (Sigma-Aldrich)] except A. fumigatus which was on Aspergillus complete medium (ACM) (Paoletti et al, 2005) and B. cinerea, on Vogel’s medium (Vogel, 1964) Where necessary, media were solidified with 2% agar
Summary
A wide range of fungi are undesirable for different reasons, including human and plant pathogens. The current arsenal of approved agents for the treatment of fungal infections is limited, with only four classes of antifungal compound targeting different structures or pathways. Their efficacy is eroded by toxicity or drug resistance (Vandeputte et al, 2012; Delarze and Sanglard, 2015; Van Dijck et al, 2018). The agrichemical industry faces concerns surrounding resistance emergence combined with tightening of fungicide regulations (Oliver and Hewitt, 2014; Coste and Vandeputte, 2015), underscoring the urgent need for new effective treatments for fungal control
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