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Novel mechanisms of azole resistance in clinical isolates of Candida glabrata

Award Number: R21AI180916
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Novel mechanisms of azole resistance in clinical isolates of Candida glabrata - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $236,772 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	2	2/13/2025	NON-COMPETING CONTINUATION	$236,772
														Subtotal = $236,772

Issue Date FY: 2024 ( Subtotal = $211,697 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	1	3/19/2024	NEW	$190,527
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	001	1	5/29/2024	NEW	$21,170
														Subtotal = $211,697

Grand Total All Awards = $448,469

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Novel mechanisms of azole resistance in clinical isolates of Candida glabrata

Award Number: R21AI180916

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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