New strategies are urgently needed to counter the threat to human health posed by drug-resistant fungi. To explore an as-yet unexploited target space for antifungals, we screened a library of protein kinase inhibitors for the ability to reverse resistance of the most common human fungal pathogen, Candida albicans, to caspofungin, a widely used antifungal. This screen identified multiple 2,3-aryl-pyrazolopyridine scaffold compounds capable of restoring caspofungin sensitivity. Using chemical genomic, biochemical, and structural approaches, we established the target for our most potent compound as Yck2, a casein kinase 1 family member. Combination of this compound with caspofungin eradicated drug-resistant C. albicans infection while sparing co-cultured human cells. In mice, genetic depletion of YCK2 caused an ∼3-log10 decline in fungal burden in a model of systemic caspofungin-resistant C. albicans infection. Structural insights and our tool compound's profile in culture support targeting the Yck2 kinase function as a broadly active antifungal strategy.

中文翻译：

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通过抑制非必需的应激激酶Yck2克服真菌对棘球and素的抗性。

迫切需要新的策略来抵抗耐药真菌对人类健康的威胁。为了探索尚未发现的抗真菌目标空间，我们筛选了蛋白激酶抑制剂库，以逆转最常见的人类真菌病原体白色念珠菌对卡泊芬净（一种广泛使用的抗真菌剂）的耐药性。该屏幕确定了多种能够恢复卡泊芬净敏感性的2,3-芳基-吡唑并吡啶支架化合物。使用化学基因组，生物化学和结构方法，我们确定了最有效的化合物酪蛋白激酶1家族成员Yck2的目标。该化合物与卡泊芬净的结合消除了耐药的白色念珠菌感染，同时保留了共同培养的人细胞。在老鼠中 在系统性耐卡泊芬净的白色念珠菌感染模型中，YCK2的遗传耗竭导致真菌负担降低约3-log10。结构见解和我们的工具化合物在培养物中的概况支持靶向Yck2激酶功能，是一种广泛有效的抗真菌策略。