# Novel Azole Resistance Mechanisms in Candida albicans

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $121,008

## Abstract

A critical barrier to progress in overcoming azole antifungal resistance in Candida albicans is the lack of a
complete understanding of its molecular and genetic basis because the known mechanisms of resistance do
not fully explain resistance observed among many clinical isolates. Our goal is to advance the treatment of
Candida infections by identifying novel azole resistance mechanisms that can be exploited to ultimately
overcome this problem. Our central hypothesis is that azole resistance in clinical isolates of C. albicans is
multifactorial and involves complex genetic changes that 1) alter azole target binding, 2) activate transcriptional
programs that impart resistance, and 3) reduce azole uptake. Our objectives are to 1) delineate the effects of
clinically relevant mutations in ERG11, alone and in combination, on the activity of its gene product, fitness,
and azole susceptibility, 2) determine the clinical significance of novel Zn(2)Cys6 transcription factors (ZCFs)
that influence azole susceptibility, and 3) to discover the determinants of reduced azole import and their
contribution to azole resistance in clinical isolates. Our preliminary data suggest that different ERG11
mutations diversely affect sterol demethylase activity, including alterations of catalytic efficiency, target binding
kinetics, and reaction velocity. We have also observed that artificial activation of a distinct set of ZCFs in C.
albicans increases azole resistance. We have identified azole-resistant clinical isolates that exhibit
transcriptional profiles consistent with activation of these ZCFs and that contain candidate activating mutations
in these ZCF genes. Finally, we have demonstrated that C. albicans takes up fluconazole by energy-
independent facilitated diffusion. We have observed that some azole resistant isolates exhibit reduced
fluconazole uptake. In Aim 1 of this proposal we will undertake genetic, microbiologic, and biochemical studies
to dissect the effects of single and combinatorial mutations in ERG11 on sterol demethylase susceptibility,
substrate affinity, azole binding, catalytic activity, and fitness. In Aim 2 we will undertake genetic and
microbiologic studies to determine if and how mutations found in the genes encoding novel ZCFs in resistant
clinical isolates result in their activation and increased azole resistance. In Aim 3 we will determine the
mechanism of azole antifungal import and its contribution to azole resistance in clinical isolates of C. albicans.
Our approach is innovative as we will determine for the first time precisely how mutations in ERG11 influence
enzyme activity, dissect combinations of mutations, and determine the impact of such mutations on fitness of
C. albicans. This work also explores novel mechanisms of azole resistance. The proposed research is
significant as it will provide the understanding needed to ultimately overcome azole resistance through the
development of improved azoles, interference with activated ZCFs...

## Key facts

- **NIH application ID:** 9948552
- **Project number:** 5R01AI058145-14
- **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:** $121,008
- **Award type:** 5
- **Project period:** 2005-06-01 → 2020-08-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948552

## Citation

> US National Institutes of Health, RePORTER application 9948552, Novel Azole Resistance Mechanisms in Candida albicans (5R01AI058145-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948552. Licensed CC0.

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