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

Cell Chem Biol. 2020 Mar 19;27(3):269-282.e5. doi: 10.1016/j.chembiol.2019.12.008. Epub 2020 Jan 7.


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.

Keywords: Candida; casein kinase; caspofungin; fungal pathogen; protein kinase inhibitor; pyrazolopyridine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology
  • Candida albicans / drug effects*
  • Candidiasis / drug therapy*
  • Cells, Cultured
  • Drug Resistance, Fungal / drug effects*
  • Echinocandins / chemistry
  • Echinocandins / pharmacology
  • Fungal Proteins / antagonists & inhibitors*
  • Fungal Proteins / metabolism
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*


  • Antifungal Agents
  • Echinocandins
  • Fungal Proteins
  • Protein Kinase Inhibitors