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

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

Caplan, Tavia;Lorente-Macías, Álvaro;Stogios, Peter J;Evdokimova, Elena;Hyde, Sabrina;Wellington, Melanie A;Liston, Sean;Iyer, Kali R;Puumala, Emily;Shekhar-Guturja, Tanvi;Robbins, Nicole;Savchenko, Alexei;Krysan, Damian J;Whitesell, Luke;Zuercher, William J;Cowen, Leah E;
cell chemical biology 2020
245
caplan2020overcomingcell

Abstract

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-log 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.

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