Related Experiment Video
Updated: Jul 31, 2025
Use of In Vivo Imaging to Screen for Morphogenesis Phenotypes in Candida albicans Mutant Strains During Active Infection in a Mammalian Host
Published on: October 12, 2022
Imaging-based screening identifies modulators of the eIF3 translation initiation factor complex in Candida albicans
Katura Metzner1, Matthew J O'Meara2, Benjamin Halligan3,4
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
Abstract:
Fungal pathogens like Candida albicans can cause devastating human disease. Treatment of candidemia is complicated by the high rate of resistance to common antifungal therapies. Additionally, there is host toxicity associated with many antifungal compounds due to the conservation between essential mammalian and fungal proteins. An attractive new approach for antimicrobial development is to target virulence factors: non-essential processes that are required for the organism to cause disease in human hosts. This approach expands the potential target space while reducing the selective pressure towards resistance, as these targets are not essential for viability. In C. albicans, a key virulence factor is the ability to transition to hyphal morphology. We developed a high-throughput image analysis pipeline to distinguish between yeast and filamentous growth in C. albicans at the single cell level. Based on this phenotypic assay, we screened the FDA drug repurposing library of 2,017 compounds for their ability to inhibit filamentation and identified 33 compounds that block the hyphal transition in C. albicans with IC 50 values ranging from 0.2 to 150 µM. Multiple compounds showed a phenyl vinyl sulfone chemotype, prompting further analysis. Of these phenyl vinyl sulfones, NSC 697923 displayed the most efficacy, and by selecting for resistant mutants, we identified eIF3 as the target of NSC 697923 in C. albicans .
Insights
Researchers screened 2,017 drugs to find compounds inhibiting *Candida albicans* filamentation, a key virulence factor. They identified 33 compounds, including phenyl vinyl sulfones, with the most effective targeting eIF3.
Area of Science:
- Microbiology
- Drug Discovery
- Molecular Biology
Background:
- *Candida albicans* causes life-threatening infections (candidemia), often resistant to standard antifungals.
- Existing antifungal drugs can be toxic due to shared targets in fungi and humans.
- Targeting virulence factors, like hyphal growth in *C. albicans*, offers a novel strategy to combat fungal infections and reduce resistance.
Approach:
- Developed a high-throughput image analysis pipeline for single-cell distinction between yeast and filamentous *C. albicans*.
- Screened the FDA drug repurposing library (2,017 compounds) using this phenotypic assay.
- Identified compounds inhibiting the hyphal transition and elucidated the target of a lead compound.
Key Points:
- Identified 33 compounds that inhibit *C. albicans* filamentation, with IC50 values from 0.2 to 150 µM.
- Discovered a phenyl vinyl sulfone chemotype among the active compounds.
- Identified eukaryotic initiation factor 3 (*eIF3*) as the molecular target of the potent phenyl vinyl sulfone, NSC 697923.
Conclusions:
- This study identifies novel inhibitors of *C. albicans* virulence, offering potential new therapeutic avenues.
- Targeting hyphal morphogenesis represents a promising strategy to overcome antifungal resistance and reduce host toxicity.
- Elucidation of the *eIF3* target provides a molecular basis for developing new antifungal agents against *C. albicans*.
