Candida albicans is a causal agent of opportunistic oral and genital infections in humans. While anti-Candida medications are currently available, the development of drug-resistance presents a significant challenge. Thus, chemical agents that can target novel pathways/enzymes essential for Candida growth would greatly enhance our capability to combat Candida infections. RNA interference (RNAi) is an evolutionarily conserved gene regulation process that operates in diverse eukaryotic organisms ranging from unicellular yeasts to mammals. Among the central components of RNAi are small interfering RNAs (siRNAs), which are processed by Dicer and incorporated into the siRNA-induced silencing complexes (siRISC) that contain Argonaute (AGO) family proteins. siRNAs guide siRISC to target RNAs, leading to sequence-specific gene silencing. The genome of Candida albicans encodes a sole catalytically active Dicer homolog (caDicer1/caDcr1) and one AGO (caAGO1). While RNAi is dispensable for cell proliferation in Candida, loss of caDcr1 blocks cell growth due to defects in caDcr1-mediated ribosomal and spliceosomal RNA maturation. These findings provide a strong rationale for our hypothesis ? small molecules that selectively inhibit the activity of caDcr1 would produce a new class of anti-Candida agents. We have established and validated a robust high-throughput screening (HTS) assay to identify small molecule inhibitors of RNAi in cultured Drosophila cells. Taking advantage of the conservation of Dicer in Candida and Drosophila and the HTS-amenable RNAi assay in cultured Drosophila cells, we propose to explore caDcr1 as a therapeutic target and to develop assays that will facilitate to identify small molecule inhibitors of caDcr1. Completion of the proposed study will generate assays that will facilitate to identify inhibitors of Candida Dicer, which may be explored further as anti-Candida compounds with clinical potential.

Public Health Relevance

Candida albicans is a causal agent of opportunistic oral and genital infections in humans, and is developing increasing resistance to existing medications. Taking advantage of the observation that the Candida RNA-processing enzyme caDcr1 is essential for cell growth, we propose to explore caDcr1 as a therapeutic target and to develop assays that will facilitate to identify small molecule inhibitors of caDcr1. Completion of the proposed study will generate assays that will facilitate to identify inhibitors of Candida Dicer, which may be explored further as anti-Candida compounds with clinical potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI131068-02
Application #
9428416
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Franceschi, Francois J
Project Start
2017-02-08
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037