# Upc2A: A Central Regulator and "Achilles' Heel" of Fluconazole Resistance in Candida glabrata

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $467,798

## Abstract

There is a significant gap in knowledge concerning the molecular and cellular underpinnings of triazole
resistance in the important fungal pathogen Candida glabrata and how such resistance might be overcome.
Our long-term goal is to improve the treatment of Candida infections by overcoming resistance to the triazole
class of antifungals. Our overall objective in the present application is to identify the target genes directly
regulated by this transcription factor, its protein interaction partners, and the genes that interact with UPC2A in
the pathogenic fungus Candida glabrata. Our preliminary data demonstrate that loss of Upc2A function in both
wild-type and triazole resistant isolates results in increased susceptibility to sterol biosynthesis inhibitors,
including a reduction in fluconazole minimum inhibitory and minimum fungicidal concentrations and enhanced
fluconazole activity by time-kill analysis. Our findings indicate that Upc2A is a key regulator of ergosterol
biosynthesis as well as other unknown processes and is essential for resistance to fluconazole in C. glabrata.
The Upc2A pathway therefore represents a potential co-therapeutic target for enhancing fluconazole activity
against this inherently resistant species and restoring and preserving this class of antifungal for the treatment
of invasive Candidiasis. In Aim 1 we will identify Upc2A target genes using transcriptional profiling (RNA-seq)
and ChIP-seq, and we will then determine which target genes influence susceptibility to fluconazole by
targeted gene disruption. In Aim 2 we will identify Upc2A interaction partner proteins using tandem affinity
purification (TAP) and will determine which of these are essential for Upc2A activity under fluconazole
exposure and which of these influence fluconazole susceptibility using targeted gene disruption. In Aim 3 of
this proposal we will undertake screens of a transposon insertion mutant library as well as a recently
developed deletion mutant library for genes that interact with, and are required for, Upc2 activation by sterol
biosynthesis inhibition in order to identify and characterize the Upc2A genetic interaction network. The
proposed studies are innovative as they uniquely focus on interference of activity of the transcription factor
Upc2A as a strategy for circumventing fluconazole resistance in C. glabrata. Moreover, our approach is
innovative as we will for the first time make use of a comprehensive set of genomic tools and techniques
designed for yeast research and apply them to clinical isolates of the fungal pathogen C. glabrata. The
proposed research is significant as it will provide new knowledge that can ultimately be exploited to overcome
triazole resistance in this inherently resistant species of Candida and restore and preserve the use of this
antifungal class for serious Candida infections.

## Key facts

- **NIH application ID:** 9852413
- **Project number:** 5R01AI131620-04
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** P. David Rogers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,798
- **Award type:** 5
- **Project period:** 2017-02-07 → 2020-08-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852413

## Citation

> US National Institutes of Health, RePORTER application 9852413, Upc2A: A Central Regulator and "Achilles' Heel" of Fluconazole Resistance in Candida glabrata (5R01AI131620-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852413. Licensed CC0.

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