Novel Combinations of Agents Targeting Translation That Synergistically Inhibit Fungal Pathogens.
Novel Combinations of Agents Targeting Translation That Synergistically Inhibit Fungal Pathogens.
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DOI：
10.3389/fmicb.2018.02355
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发表时间：
2018
影响因子：
5.2
通讯作者：
Avery SV
中科院分区：
文献类型：
--
作者：
Vallières C;Raulo R;Dickinson M;Avery SV
目前，一系列杀真菌剂或抗真菌剂被用于控制农业或医学中的真菌，但对当前药剂的耐药性正在增长，因此迫切需要新的方法和分子靶标。最近，发现不同的氨基糖苷类抗生素与特定的转运抑制剂结合，通过协同增加mRNA翻译的错误率，产生强烈的协同生长抑制真菌。在这里，专注于翻译保真度作为一个新的目标组合抗真菌治疗，我们测试的假设，即已知影响功能性氨基酸的可用性的替代组合剂将协同抑制主要真菌病原体的生长。我们筛选了172个新的组合对三种植物病原菌（立枯丝核菌、三孢发酵壳菌和灰葡萄孢菌）和三种人类病原体（新型隐球菌、白色念珠菌和烟曲霉），显示48种组合强烈抑制病原体的生长;生长抑制作用是显着更大的药物组合比一个简单的产品，他们的个别影响，在同一时间剂量其中，23种组合对一种以上的病原体有效，包括包含食品和药物批准的化合物的组合，例如，奎宁和碳酸氢盐，奎宁和潮霉素。这些组合[部分抑制组合（FIC）指数≤0.5]在单独作用可忽略不计的药物浓度下，真菌生长产量降低高达100%。对细菌、植物或哺乳动物细胞没有明显的协同作用，表明对真菌具有特异性。奎宁+潮霉素的作用模式分析表明协同误译是抗真菌机制。这种机制并不普遍，因为碳酸氢盐通过增加药物摄取而加剧了奎宁的作用。该研究揭示了化学组合和具有控制多种真菌病原体潜力的目标过程，并建议重新利用当前几种治疗方法的可能性。
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.
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DOI：
10.1073/pnas.95.23.13771
发表时间：
1998-11-10
影响因子：
11.1
作者：
Gallant, JA;Lindsley, D
通讯作者：
Lindsley, D
影响因子：
4.5
作者：
Fan-Minogue, Hua;Bedwell, David M.
通讯作者：
Bedwell, David M.
DOI：
10.1007/s10482-013-9921-5
发表时间：
2013-07-01
影响因子：
2.6
作者：
Joshi, C. V.;Pathan, E. K.;Deshpande, M. V.
通讯作者：
Deshpande, M. V.
影响因子：
2.6
作者：
Foucquier, Julie;Guedj, Mickael
通讯作者：
Guedj, Mickael
影响因子：
3.3
作者：
Alhebshi A;Sideri TC;Holland SL;Avery SV
通讯作者：
Avery SV