Novel, Synergistic Antifungal Combinations that Target Translation Fidelity.
Novel, Synergistic Antifungal Combinations that Target Translation Fidelity.
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DOI：
10.1038/srep16700
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发表时间：
2015-11-17
影响因子：
4.6
通讯作者：
Avery SV
中科院分区：
文献类型：
--
作者：
Moreno-Martinez E;Vallieres C;Holland SL;Avery SV
随着对现有治疗的耐药性增长，对新的抗真菌或杀真菌剂治疗的需求未得到满足。联合治疗有助于对抗耐药性。在这里，我们开发了一种新的，有效的联合抗真菌治疗的目标。不同的氨基糖苷类抗生素与不同的硫酸盐转运抑制剂结合，对几种真菌产生了强烈的协同生长抑制作用。联合用药使各自的MIC降低≥8倍。协同作用被抑制在酵母突变体耐硫酸盐模拟物（如铬酸盐或铬酸盐）对硫酸盐运输的影响。通过不同的机制，氨基糖苷类和硫酸盐转运的抑制导致mRNA翻译错误。当药物组合使用时，错误翻译率被刺激高达10倍，这与协同作用的模式一致。一系列不需要的真菌对这些组合的协同抑制敏感，包括人类病原体白色念珠菌、念珠菌属和念珠菌属。glabrata和新型隐球菌，食品腐败生物Zygosaccharomycesbailii和植物病原体立枯丝核菌和Zymoseptoriatrivali。由于某些真菌不受影响，因此具有一定的特异性。对细菌或哺乳动物细胞没有协同作用。结果表明，翻译保真度是用于组合治疗不期望的真菌的有希望的新靶标，与单独的每种药剂相比，所述组合需要显著降低剂量的活性组分。
There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone.