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Updated: May 11, 2025
Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
Published on: December 28, 2017
Hotspot gene conversion between FKS1 and FKS2 in echinocandin resistant Candida glabrata serial isolates
Christopher Zajac1, Nancy E Scott1,2, Susan Kline3
1Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
Abstract:
Candida glabrata (Nakaseomyces glabratus) is the most common cause of drug-resistant candidemia and is associated with a high mortality rate. Only a few mechanisms of drug resistance are known in C. glabrata, predominantly involving recurrent single nucleotide polymorphisms. The importance of structural variation in acquired drug resistance is not understood. We performed comparative phenotypic and genomic analyses of six serial bloodstream isolates of C. glabrata and identified novel mutations associated with resistance to echinocandins. Critically, we identified a novel gene conversion event between the hotspot 2 regions of FKS1 and FKS2 that was associated with increased resistance to micafungin. We further analyzed 621 publicly available C. glabrata genomes and found three additional examples of structural variation involving FKS1 and FKS2. Ultimately, drug resistance in C. glabrata involves structural variants that are missed with current diagnostic methods and need to be considered when designing and implementing more effective antifungal management strategies.
Insights
Drug-resistant Candida glabrata infections are deadly. This study reveals that structural variations, not just single mutations, drive echin অ্যাকিনোক্যান্ডিন resistance, impacting treatment strategies.
Area of Science:
- Medical Mycology
- Genomics
- Antimicrobial Resistance
Background:
- Candida glabrata (Nakaseomyces glabratus) is a leading cause of drug-resistant candidemia with high mortality.
- Existing knowledge of C. glabrata drug resistance mechanisms primarily focuses on single nucleotide polymorphisms.
- The role of structural variations in acquired drug resistance remains largely unexplored.
Purpose of the Study:
- To investigate the contribution of structural variations to echinocandin resistance in Candida glabrata.
- To identify novel genetic mechanisms underlying drug resistance in C. glabrata bloodstream isolates.
Main Methods:
- Comparative phenotypic and genomic analyses of six serial C. glabrata bloodstream isolates.
- Identification and characterization of novel mutations and structural variations.
- Analysis of 621 publicly available C. glabrata genomes to identify additional structural variations.
Main Results:
- Novel mutations conferring resistance to echinocandins were identified in C. glabrata.
- A novel gene conversion event between FKS1 and FKS2 hotspots was associated with increased micafungin resistance.
- Three additional instances of structural variation involving FKS1 and FKS2 were found in public genome data.
Conclusions:
- Structural variants, often overlooked by current diagnostic methods, play a significant role in drug resistance in C. glabrata.
- Understanding these structural variations is crucial for developing effective antifungal treatment strategies.
- Future diagnostic and therapeutic approaches must account for structural variation in C. glabrata.
