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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, Michigan, 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 toward 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 IC50 values ranging from 0.2 to 150 μM. Multiple compounds showed a phenyl sulfone chemotype, prompting further analysis. Of these phenyl 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 that inhibit Candida albicans filamentation, a key virulence factor. They identified 33 compounds, including phenyl sulfones, with NSC 697923 targeting eIF3.
Area of Science:
- Microbiology
- Mycology
- Infectious Diseases
Background:
- Candida albicans causes candidemia, often resistant to antifungals.
- Antifungal drugs face toxicity due to conserved host-fungal proteins.
- Targeting virulence factors offers a novel antimicrobial strategy with reduced resistance pressure.
Purpose of the Study:
- To identify compounds inhibiting Candida albicans hyphal morphogenesis, a crucial virulence factor.
- To screen the FDA drug repurposing library for antifungal agents targeting hyphal transition.
- To identify the molecular target of effective compounds, such as phenyl sulfones.
Main Methods:
- Developed a high-throughput image analysis pipeline for single-cell yeast-to-hyphae transition detection.
- Screened 2,017 FDA-approved drugs for inhibition of C. albicans filamentation.
- Identified effective compounds and used resistant mutant selection to determine drug targets.
Main Results:
- Identified 33 compounds inhibiting C. albicans hyphal transition, with IC50 values from 0.2 to 150 μM.
- Observed a phenyl sulfone chemotype among effective inhibitors.
- Determined that eIF3 is the molecular target of the potent phenyl sulfone NSC 697923.
Conclusions:
- Inhibiting C. albicans hyphal transition is a viable strategy for novel antifungal drug development.
- NSC 697923, a phenyl sulfone, effectively inhibits filamentation by targeting eIF3.
- This study provides new drug leads and a target for combating candidemia.
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