# Critical Factors Influencing Echinocandin Resistance in Candida glabrata

> **NIH NIH R01** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2020 · $710,571

## Abstract

Invasive fungal infections are a major cause of global morbidity and mortality, accounting for nearly 1.4
million deaths a year. Bloodstream fungal infections, largely caused by yeasts of the Candida genus, are
associated with high mortality rates (45-75%) and pose a serious threat to immunocompromised individuals,
including cancer patients, organ transplant recipients, premature infants, and AIDS patients. The echinocandin
drugs, first approved for clinical use in 2001, are an essential part of our limited antifungal drug armamentarium
and are broadly active against Candida species. These drugs block fungal glucan synthase, an enzyme
catalysing the biosynthesis of β-1,3 glucan, a major structural component of the fungal cell wall. Echinocandin
resistance resulting in clinical failures arises due to mutations in the “hot spot” regions of genes FKS1 and FKS2,
which encode β-1,3 glucans synthase subunits. While most Candida spp. have shown a consistently low
frequency of echinocandin resistance (1-3%), Candida glabrata has been an exception, with some transplant
centers reporting C. glabrata echinocandin resistance rates of 10-15%. Echinocandin resistance always arises
during therapy and is expected to increase further, as expanding numbers of patients are exposed to antifungal
prophylaxis and echinocandin class drugs become generic. Furthermore, C. glabrata incidence has been
increasing and it now is the second most prevalent fungal pathogen after C. albicans in North America and
Europe. Thus, there is an urgent need to better understand the factors that contribute to emergence of
echinocandin resistance in C. glabrata. This proposal centers around the hypothesis, based on recent studies
published by our lab and others, that emergence of resistance is preceded by two stages: tolerance, where
multiple cellular factors stabilize C. glabrata during drug exposure, and escape, where echinocandin-resistant
fks mutations develop in the drug-tolerant cells. We propose to identify factors contributing to both of these
stages by the following complementary approaches: (1) testing the roles of candidate genes in drug tolerance
and development of resistance (escape) in vitro and validating them in vivo, and (2) identifying genetic
polymorphisms that influence drug tolerance and escape in our extensive collection of C. glabrata clinical isolates
(~1000 strains) derived from diverse geographical locations in the U.S. and around the globe. For each approach,
we will utilize our well-defined in vitro assays and recently developed clinically-relevant gastrointestinal
colonization and intraabdominal abscess models that mimic resistance emergence in humans. Together, these
approaches will define critical features of the underlying biology of an important fungal pathogen and identify
targets that can improve therapeutic success and prevent development of resistance. Furthermore,
understanding determinants of tolerance and resistance in clinical C. glabrata strains wi...

## Key facts

- **NIH application ID:** 9983583
- **Project number:** 5R01AI109025-08
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** David S Perlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $710,571
- **Award type:** 5
- **Project period:** 2019-03-22 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983583

## Citation

> US National Institutes of Health, RePORTER application 9983583, Critical Factors Influencing Echinocandin Resistance in Candida glabrata (5R01AI109025-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983583. Licensed CC0.

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