# Novel mechanisms of azole resistance in clinical isolates of Candida glabrata

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2024 · $211,697

## Abstract

Candida glabrata is the second most common cause of candidemia. Many studies have found
that patients with C. glabrata bloodstream infection have higher mortality than those infected
with other Candida spp. One potential cause of this increased mortality is the relative ease with
which C. glabrata can acquire resistance to antifungal agents, including the major antifungal
drug fluconazole (FLC). In vitro studies with a limited number of clinical isolates have led to the
conclusion that that C. glabrata develops FLC resistance by one of two mechanisms, petite
mutants with mitochondrial defects or gain-of-function mutations in the Pdr1 transcription factor,
which result in overexpression of genes encoding drug efflux pumps. These conclusions are
based on the analysis of a relatively small number of C. glabrata isolates that were performed in
vitro. We analyzed 19 different C. glabrata clinical isolates with elevated FLC minimal inhibitory
concentrations (MICs) by whole genome sequencing and Western blotting for proteins involved
in FLC resistance. While a majority of these strains do contain alterations in their PDR1
sequence, most of these mutations have not been associated with FLC resistance previously.
Additionally, we found 4 unrelated strains with changes in ERG11, and 3 of these strains had
the same mutation, strongly suggesting that mutations in this gene may also reduce FLC
susceptibility. We also analyzed the transcriptional response of C. glabrata to FLC in the mouse
model of disseminated infection and found that the organism responds significantly different to
this drug during mammalian infection relative to growth in vitro. We will explore these compelling
data by 1) performing functional analysis of the genomes of clinical C. glabrata isolates with
elevated FLC MICs, and 2) analyzing the effects of FLC treatment on the C. glabrata
transcriptome during mammalian infection. Successful completion of these two aims will
important new insight into the molecular basis of FLC resistance in C. glabrata as it infects the
mammalian host. This information will serve as the basis for developing new strategies to
combat antifungal resistance in this increasingly prevalent pathogen.

## Key facts

- **NIH application ID:** 10888857
- **Project number:** 1R21AI180916-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** W Scott Moye-Rowley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $211,697
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888857

## Citation

> US National Institutes of Health, RePORTER application 10888857, Novel mechanisms of azole resistance in clinical isolates of Candida glabrata (1R21AI180916-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10888857. Licensed CC0.

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