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Multi-omics Analysis of Experimentally Evolved Candida auris Isolates Reveals Modulation of Sterols, Sphingolipids, and Oxidative Stress in Acquired Amphotericin B Resistance

Summary

Researchers studied how the fungus Candida auris develops resistance to amphotericin B, an important antifungal drug. By evolving two laboratory strains of this fungus under drug pressure, they discovered two different ways the fungus can become resistant: one through stress management genes, the other through changes in its protective lipids. These findings help explain why some clinical infections with this dangerous fungus are so hard to treat.

Background

Candida auris is a multidrug-resistant pathogenic fungus with high prevalence of amphotericin B (AmB) resistance, an uncommon trait in most Candida species. While alterations in ergosterol biosynthesis contribute to AmB resistance in laboratory strains, mechanisms in clinical isolates remain poorly understood. This study investigates molecular mechanisms underlying acquired AmB resistance in experimentally evolved C. auris isolates.

Objective

To identify genetic, genomic, transcriptomic, and lipidomic changes associated with acquired amphotericin B resistance in experimentally evolved Candida auris Clade II isolates. The study aims to characterize both sterol-dependent and sterol-independent resistance mechanisms.

Results

Two distinct resistance mechanisms were identified: the A1.1 lineage developed resistance through AOX2 upregulation and mutations in UPC2 and RTG3 transcription factors with reduced oxidative stress; the B1.1 lineage developed resistance through enhanced ergosterol biosynthesis, ERG6 K371N mutation, and HSX11 downregulation leading to reduced glucosylceramides. AOX2 deletion reversed resistance in both adapted strains and prevented adaptation under experimental conditions.

Conclusion

Amphotericin B resistance in C. auris can be acquired through both sterol-dependent and sterol-independent mechanisms, with AOX2, UPC2, and RTG3 identified as key regulators. The findings highlight the complex interplay between oxidative stress responses, sterol metabolism, sphingolipid modulation, and cell wall integrity in mediating AmB resistance, with implications for understanding clinical resistance.
  • Published in:Molecular Microbiology,
  • Study Type:Experimental Evolution Study,
  • Source: PMID: 40468551, DOI: 10.1111/mmi.15379
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