The development of effective antifungal therapeutics remains a formidable challenge because of the close evolutionary relationship between humans and fungi. Mitochondrial function may present an exploitable vulnerability because of its differential utilization in fungi and its pivotal roles in fungal morphogenesis, virulence, and drug resistance already demonstrated by others. We now report mechanistic characterization of ML316, a thiohydantoin that kills drug-resistant Candida species at nanomolar concentrations through fungal-selective inhibition of the mitochondrial phosphate carrier Mir1. Using genetic, biochemical, and metabolomic approaches, we established ML316 as the first Mir1 inhibitor. Inhibition of Mir1 by ML316 in respiring yeast diminished mitochondrial oxygen consumption, resulting in an unusual metabolic catastrophe marked by citrate accumulation and death. In a mouse model of azole-resistant oropharyngeal candidiasis, ML316 reduced fungal burden and enhanced azole activity. Targeting Mir1 could provide a new, much-needed therapeutic strategy to address the rapidly rising burden of drug-resistant fungal infection.

由于人类与真菌之间的密切进化关系，有效的抗真菌治疗剂的开发仍然是一个艰巨的挑战。线粒体功能可能存在可利用的脆弱性，因为它在真菌中的差异利用以及在真菌形态发生，毒力和耐药性中的关键作用已经被其他人证实。现在，我们报告ML316（一种硫羟乙内酰脲，其杀死抗药性念珠菌）的机械特征通过真菌选择性抑制线粒体磷酸盐载体Mir1，在纳摩尔浓度下对各种物种进行了鉴定。使用遗传，生化和代谢组学方法，我们将ML316建立为第一个Mir1抑制剂。ML316在呼吸酵母中对Mir1的抑制作用减少了线粒体的氧气消耗，从而导致了以柠檬酸盐积累和死亡为特征的异常代谢灾难。在抗唑类口咽念珠菌病的小鼠模型中，ML316减少了真菌负担并增强了吡咯活性。靶向Mir1可以提供一种新的，急需的治疗策略，以解决耐药真菌感染迅速增加的负担。