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

Caplan, Tavia; Lorente-Macias, Alvaro; 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;

Publicación: CELL CHEMICAL BIOLOGY
2020
VL / 27 - BP / 269 - EP / +
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 similar to 3-log(10) 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.

Access level

Green accepted, Bronze