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Updated: Aug 27, 2025
Small-Scale Plasma Membrane Preparation for the Analysis of Candida albicans Cdr1-mGFPHis
Published on: June 13, 2021
High-resolution crystal structure and chemical screening reveal pantothenate kinase as a new target for antifungal
Shalev Gihaz1, Peter Gareiss2, Jae-Yeon Choi1
1Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Abstract:
Fungal infections are the leading cause of mortality by eukaryotic pathogens, with an estimated 150 million severe life-threatening cases and 1.7 million deaths reported annually. The rapid emergence of multidrug-resistant fungal isolates highlights the urgent need for new drugs with new mechanisms of action. In fungi, pantothenate phosphorylation, catalyzed by PanK enzyme, is the first step in the utilization of pantothenic acid and coenzyme A biosynthesis. In all fungi sequenced so far, this enzyme is encoded by a single PanK gene. Here, we report the crystal structure of a fungal PanK alone as well as with high-affinity inhibitors from a single chemotype identified through a high-throughput chemical screen. Structural, biochemical, and functional analyses revealed mechanisms governing substrate and ligand binding, dimerization, and catalysis and helped identify new compounds that inhibit the growth of several Candida species. The data validate PanK as a promising target for antifungal drug development.
Insights
New antifungal drugs are urgently needed due to rising resistance. Researchers discovered novel inhibitors targeting the fungal PanK enzyme, a key component in coenzyme A biosynthesis, showing promise for treating Candida infections.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Fungal infections cause significant mortality, with increasing multidrug resistance necessitating novel therapeutic strategies.
- Pantothenate kinase (PanK) is crucial for fungal pantothenic acid and coenzyme A biosynthesis, making it a potential drug target.
- Existing treatments face challenges from emerging resistant fungal strains.
Purpose of the Study:
- To elucidate the structural and functional mechanisms of fungal PanK.
- To identify and characterize novel high-affinity inhibitors of fungal PanK.
- To validate PanK as a viable target for developing new antifungal agents.
Main Methods:
- High-throughput chemical screening to identify inhibitor chemotypes.
- X-ray crystallography to determine the structure of fungal PanK with inhibitors.
- Biochemical assays to analyze enzyme kinetics and ligand binding.
- Functional assays to assess the efficacy of inhibitors against Candida species.
Main Results:
- The crystal structure of fungal PanK, alone and bound to inhibitors, was determined.
- Mechanisms of substrate binding, ligand interaction, dimerization, and catalysis were elucidated.
- Novel compounds were identified that exhibit high affinity for PanK.
- These compounds demonstrated inhibitory effects on the growth of multiple Candida species.
Conclusions:
- Fungal PanK is a validated and promising target for antifungal drug discovery.
- Structural insights provide a foundation for rational drug design against PanK.
- The identified inhibitors represent a new chemotype with potential for treating invasive fungal infections.
