Chemoproteomic Profiling of <i>C. albicans</i> for Characterization of Antifungal Kinase Inhibitors
<i>Candida albicans</i> is a major cause of systemic candidiasis, a severe fungal infection with a ∼40% mortality rate. Yck2, a casein kinase 1 (CK1) in <i>C. albicans</i>, is targeted by antifungal inhibitors YK-I-02 (YK) and MN-I-157 (MN). Using multiplexed inhibitor beads and mass spectrometry (MIB/MS), the selectivity of these inhibitors was determined across the fungal kinome. The MIB matrix captured 89% of <i>C. albicans</i> protein kinases, revealing that YK and MN selectively engage three CK1 homologues (Yck2, Yck22, and Hrr25) and a human p38α homologue (Hog1). Chemoproteomics using a custom MN-kinobead confirmed the remarkable fungal kinome selectivity. To identify new Yck2 inhibitors with selectivity over Hog1, 13 human CK1 inhibitors were screened, leading to the discovery of a new chemotype with antifungal activity. These findings highlight the utility of MIB/MS in profiling nonhuman kinomes and developing selective fungal kinase inhibitors as antimicrobial agents.
Authors
- Zhongle Liu (ORCID: https://orcid.org/0000-0003-4198-8214)
- Emily Puumala (ORCID: https://orcid.org/0009-0008-3371-5877)
- Nicole Robbins (ORCID: https://orcid.org/0000-0003-2821-9269)
- Angie L. Mordant (ORCID: https://orcid.org/0000-0002-0151-4498)
- Luke J. Whitesell (ORCID: https://orcid.org/0000-0001-6445-5766)
- Scott K. Lyons (ORCID: https://orcid.org/0000-0003-0139-6054)
- Leah E. Cowen (ORCID: https://orcid.org/0000-0001-5797-0110)
- Laura E. Herring (ORCID: https://orcid.org/0000-0003-4496-7312)
- Rafael M. Couñago (ORCID: https://orcid.org/0000-0003-1847-5090)
- Aurora Cabrera
- David J. Shirley
- Meganathan Nandakumar (ORCID: https://orcid.org/0000-0002-9093-2244)
- David H. Drewry (ORCID: https://orcid.org/0000-0001-5973-5798)
- Timothy M. Willson (ORCID: https://orcid.org/0000-0003-4181-8223)
- Lee M. Graves (ORCID: https://orcid.org/0000-0002-4736-9855)
- Jeffery L. Smith (ORCID: https://orcid.org/0000-0003-2189-0420)
- Bonnie Yiu
Institutions
- University of North Carolina at Chapel Hill (US)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- University of Toronto (CA)
- Structural Genomics Consortium (CA)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00097
- Citations
- 6
- Primary Topic
- Antifungal resistance and susceptibility
- Type
- article
- Field-Weighted Citation Impact
- 8.38
Funders
- Boehringer Ingelheim
- Bristol-Myers Squibb
- Pfizer
- Bayer
- North Carolina Biotechnology Center
- Genome Canada
- Merck KGaA
- Takeda Foundation
- Ontario Genomics Institute
- Innovative Medicines Initiative
- National Institutes of Health
- Genentech
- Janssen Biotech