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 ?-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 ?-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 will lead to potential diagnostic assays to track the molecular epidemiology of high-threat strains.

Public Health Relevance

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. The prevalence of drug-resistant C. glabrata infections has been rising, but the reasons for this fungus readily developing resistant mutations are not clear. This proposal seeks to define critical features of the underlying biology of C. glabrata that impinges on the development of drug resistance.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
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Love, Dona
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Hackensack University Medical Center
United States
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Taj-Aldeen, Saad J; Salah, Husam; Perez, Winder B et al. (2018) Molecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar. Antimicrob Agents Chemother 62:
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Zhao, Yanan; Nagasaki, Yoji; Kordalewska, Milena et al. (2016) Rapid Detection of FKS-Associated Echinocandin Resistance in Candida glabrata. Antimicrob Agents Chemother 60:6573-6577
Healey, Kelley R; Zhao, Yanan; Perez, Winder B et al. (2016) Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat Commun 7:11128
Healey, Kelley R; Jimenez Ortigosa, Cristina; Shor, Erika et al. (2016) Genetic Drivers of Multidrug Resistance in Candida glabrata. Front Microbiol 7:1995

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