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Directed Evolution Detects Supernumerary Centric Chromosomes Conferring Resistance to Azoles in Candida auris
Aswathy Narayanan1, Praveen Kumar2, Anshu Chauhan2
1Molecular Mycology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, Karnataka, India.
Mbio
|November 29, 2022
Summary
Candida auris develops fluconazole resistance through novel chromosome duplication events and gene amplification. This study reveals both aneuploidy-driven and independent mechanisms contributing to antifungal resistance in this superbug.
Area of Science:
- Medical Mycology
- Antimicrobial Resistance
- Genetics
Background:
- Candida auris is a multidrug-resistant fungal pathogen causing severe infections, particularly in immunocompromised individuals.
- While most East Asian clade 2 isolates are drug-susceptible, understanding resistance mechanisms is crucial for global health.
- Antifungal resistance can arise through mutations, gene copy number changes, or altered gene expression.
Purpose of the Study:
- To investigate the mechanisms of fluconazole resistance development in a drug-susceptible Candida auris isolate.
- To analyze genomic and transcriptomic changes associated with acquired drug resistance.
- To identify novel pathways contributing to antifungal resistance in C. auris.
Main Methods:
- Experimental evolution of a drug-susceptible C. auris isolate in the presence of fluconazole over multiple generations.
- Next-generation sequencing and electrophoretic karyotyping to analyze chromosomal and DNA sequence alterations.
- Transcriptome analysis to identify changes in gene expression profiles.
Main Results:
- Two evolved isolates developed fluconazole resistance via segmental aneuploidy, forming supernumerary chromosomes from duplicated regions of chromosome 5, including centromeres.
- Loss of these supernumerary chromosomes fully restored fluconazole susceptibility.
- A third isolate exhibited fluconazole resistance through overexpression of drug efflux pumps, a non-aneuploidy-driven mechanism.
Conclusions:
- Candida auris can acquire fluconazole resistance through both aneuploidy-driven (supernumerary chromosomes) and aneuploidy-independent (gene expression changes) mechanisms.
- Emergence of centric supernumerary chromosomes provides a stable mechanism for gene amplification and azole resistance.
- These findings highlight the adaptability of C. auris and the diverse strategies it employs to overcome antifungal treatments.
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