Wednesday, October 15, 2025 10/15/2025

Critical Factors Influencing Echinocandin Resistance in Candida glabrata

Award Number: R01AI109025
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: 08/01/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Critical Factors Influencing Echinocandin Resistance in Candida glabrata - Fungal pathogens cause a tremendous health burden worldwide and are associated with over 1.5 million deaths per year globally, eclipsing or equaling malaria, TB, or HIV. The last several decades have seen a shift in the epidemiology of Candida infections, with a decreased incidence of pan-sensitive C. albicans and a concomitant increase in non-albicans Candida species, such as C. glabrata and C. parapsilosis, which either have reduced intrinsic sensitivity to commonly used antifungals or can rapidly acquire drug-resistant mutations. Echinocandins are inhibitors of b-glucan synthase (GS) that are cidal in Candida and well tolerated by patients and are thus used as first-line agents for invasive Candida infections, especially in light of increasing insensitivity to azoles in species such as C. glabrata. However, resistance to echinocandins is also increasing, and in C. glabrata it is the highest among major Candida pathogens (including C. auris). Clinical echinocandin resistance (ECHR) is associated with mutations in genes encoding GS, FKS1 and FKS2, and C. glabrata can rapidly evolve ECHR mutations both in vitro and during patient treatment. However, the cellular mechanisms underpinning this rapid emergence of resistance are not well understood. Previously, we described a universal paradigm for fungi, in which drug exposure by a cidal agent effectively kills susceptible cells but leaves a sub-population of viable non- growing cells that are drug-tolerant. Ultimately, some drug-tolerant cells escape drug action by forming heritable drug resistant mutations. We have identified the gastrointestinal (GI) tract and macrophages as important in-host niches of echinocandin-tolerant C. glabrata, in which ECHR mutants form. We have also shown that the evolution of resistance to the echinocandin caspofungin in the GI tract is more complex than was previously appreciated, involving formation of mutations in FEN1, a sphingolipid biosynthesis gene. Importantly, we also identified fen1 mutations in multiple clinical isolates, where they contribute to reduced caspofungin susceptibility. Finally, we discovered that reactive oxygen species (ROS) are formed in C. glabrata cells during echinocandin treatment. However, genes involved in ROS detoxification are downregulated, and deletion of several such genes greatly induces the formation of ECHR mutations, suggesting that ROS induction is a programmed C. glabrata response that may promote the emergence of resistance. In this grant we propose to use transposon insertion screening to comprehensively identify C. glabrata vulnerabilities specific to the host niches where echinocandin tolerance and resistance occur (Aim 1), to comprehensively define the clinically relevant mutational routes to tolerance and resistance against multiple echinocandins in the gut (Aim 2), and to use accurate multidisciplinary complementary approaches, including electron paramagnetic/spin resonance (EPR/ESR) and in vivo ROS reporters, to clearly identify the type(s) of ROS, their role(s), and their source(s) in C. glabrata during echinocandin treatment (Aim 3). By identifying and validating cellular vulnerabilities important for drug tolerance, it will be possible to devise intervention strategies downstream that prevent resistance.


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 = $2,558,055 )
2025	2025	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	13	8/13/2025	EXTENSION WITH OR WITHOUT FUNDS	$2,558,055
2025	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	12	8/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,558,055

Issue Date FY: 2024 ( Subtotal = $541,534 )
2024	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	12	7/2/2024	NON-COMPETING CONTINUATION	$837,746
2024	2022	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	10	7/12/2024	NON-COMPETING CONTINUATION	$0
2024	2018	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	5	10/1/2023	COMPETING CONTINUATION	-$296,212
														Subtotal = $541,534

Issue Date FY: 2023 ( Subtotal = $857,021 )
2023	2023	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	11	6/26/2023	COMPETING CONTINUATION	$857,021
														Subtotal = $857,021

Issue Date FY: 2022 ( Subtotal = $710,571 )
2022	2022	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	10	7/20/2022	NON-COMPETING CONTINUATION	$710,571
														Subtotal = $710,571

Issue Date FY: 2021 ( Subtotal = $710,571 )
2021	2021	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	9	7/15/2021	NON-COMPETING CONTINUATION	$710,571
														Subtotal = $710,571

Issue Date FY: 2020 ( Subtotal = $710,571 )
2020	2020	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	8	7/10/2020	NON-COMPETING CONTINUATION	$710,571
														Subtotal = $710,571

Issue Date FY: 2019 ( Subtotal = $1,045,685 )
2019	2019	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	007	7	7/25/2019	NON-COMPETING CONTINUATION	$710,571
2019	2018	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	004	6	5/31/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$380,639
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	008	5	8/5/2019	COMPETING CONTINUATION	$296,212
2019	2018	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Allergy and Infectious Diseases Research	005	6	6/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$551,635
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	002	5	4/24/2019	COMPETING CONTINUATION	$551,635
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	003	5	5/31/2019	COMPETING CONTINUATION	-$341,737
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	006	5	6/10/2019	COMPETING CONTINUATION	-$551,635
2019	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	001	4	4/24/2019	NON-COMPETING CONTINUATION	-$524,999
2019	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	3	4/24/2019	NON-COMPETING CONTINUATION	-$26,636
														Subtotal = $1,045,685

Issue Date FY: 2018 ( Subtotal = $637,949 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	5	5/14/2018	COMPETING CONTINUATION	$637,949
														Subtotal = $637,949

Issue Date FY: 2017 ( Subtotal = $524,999 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	4	7/28/2017	NON-COMPETING CONTINUATION	$524,999
														Subtotal = $524,999

Issue Date FY: 2016 ( Subtotal = $524,999 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	3	7/11/2016	NON-COMPETING CONTINUATION	$524,999
														Subtotal = $524,999

Issue Date FY: 2015 ( Subtotal = $524,999 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	7/16/2015	NON-COMPETING CONTINUATION	$524,999
														Subtotal = $524,999

Issue Date FY: 2014 ( Subtotal = $487,650 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	7/25/2014	NEW	$487,650
														Subtotal = $487,650

Grand Total All Awards = $9,834,604

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Critical Factors Influencing Echinocandin Resistance in Candida glabrata

Award Number: R01AI109025

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: 08/01/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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