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Echinocandin Cross-resistance and Hetero-resistance

Award Number: R21AI199117
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: 06/25/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Echinocandin Cross-resistance and Hetero-resistance - Summary Echinocandins are an important class of antifungals used to treat life-threatening fungal infections such as candidemia and invasive candidiasis. Though usually effective, mortality still ranges from 20% to 40% largely due to mutations that arise within the drug targets (encoded by FKS genes) that cause resistance. Mutations in the hotspot-1 region of FKS genes generally confer cross-resistance (CR) to all echinocandins and are associated with poor clinical outcomes. This project investigates the question of whether echinocandin susceptibility can be restored to CR mutants by targeting other gene products. Such genes will be identified by performing the genome-wide Tn-seq screens in two different CR derivatives of the yeast Candida glabrata, a common opportunistic pathogen. Preliminary Tn-seq screens identified dozens of candidate genes and several known inhibitors that will be evaluated judiciously for their ability to mitigate CR to echinocandins. Surprisingly, super-cross-resistance (super-CR) was conferred in both the FKS1F625∆ and FKS2F659∆ derivatives by disrupting a small number of genes with transposons, suggesting that endogenous inhibitors of the FKS genes were lost. The strongest inhibitor of FKS1F625∆ was FKS2 and the strongest inhibitor of FKS2F659∆ was FKS1, which confirms earlier reports of mutual antagonism between the FKS gene products. Similar super-CR derivatives of C. glabrata and C. albicans have been recovered previously from echinocandin-treated patients and from in vitro evolution experiments. To better understand the mutual antagonism mechanism that prevents super-CR and to determine whether other genes and their inhibitors can mitigate super-CR, additional Tn-seq screens will be performed. The results will also shed light on the mechanism responsible for FKS mutual antagonism. In another surprise, only one of the two CR derivatives (FKS2F659∆ mutant) was found to exhibit heteroresistance (HR) to echinocandins while the other (FKS1F625∆ mutant) did not. HR occurs when the majority of cells in a clonal population remain susceptible to echinocandins, and a small minority exhibit the resistance phenotype. Though HR contributes to breakthrough infections of C. parapsilosis, the mechanism that governs phenotypic switching between susceptible and resistant states is not understood. To help elucidate this mechanism, the Tn-seq experiments described above in C. glabrata will be reanalyzed and candidate genes will be retested using specific assays of HR in addition to CR. Preliminary results indicate an FDA approved compound can prevent this type of HR in vitro and potentially can be repurposed to mitigate HR and CR in patients. This pioneering project may quickly lead to improved clinical outcomes and serve as a paradigm for researching similar processes in other human pathogens.


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: 2026 ( Subtotal = $412,324 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	6/25/2026	NEW	$412,324
														Subtotal = $412,324

Grand Total All Awards = $412,324

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Echinocandin Cross-resistance and Hetero-resistance

Award Number: R21AI199117

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: 06/25/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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