Overcoming Fungal Echinocandin Resistance through Inhibition of the Non-essential Stress Kinase Yck2

摘要

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-resistantC. albicansinfection while sparing co-cultured human cells. In mice, genetic depletion ofYCK2caused an ∼3-log10decline in fungal burden in a model of systemic caspofungin-resistantC. albicansinfection. Structural insights and our tool compound's profile in culture support targeting the Yck2 kinase function as a broadly active antifungal strategy.