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Genotype-Phenotype Relationships in Azole-Resistant Aspergillus: Two Sides of the Same Coin
Merlijn H I van Haren1, Willem J G Melchers1, Jianhua Zhang1
1Department of Medical Microbiology, Radboudumc Community for Infectious Diseases, Radboudumc, 6525 GA Nijmegen, The Netherlands.
Abstract:
Aspergillus fumigatus is a leading cause of invasive fungal disease in humans and is classified as a critical priority threat by the World Health Organization. Triazole antifungals remain the cornerstone of therapy, yet their effectiveness is steadily being eroded by the continuous rise in drug resistance. Most resistance mechanisms trace back to mutations in Cyp51A, spawning well-defined genotypes such as TR34/L98H and TR46/Y121F/T289A. However, the Cyp51A genotype-phenotype landscape in A. fumigatus is far from straightforward. Isolates that share an identical TR genotype can display strikingly divergent susceptibility profiles, and mutational hotspots in Cyp51A, such as G54, M220 and G448, are linked to varying resistances, challenging assumptions about predictable resistance behavior. Complicating matters further, an expanding array of resistance mechanisms, independent of Cyp51A, is now being uncovered. This review summarizes the current state of knowledge on azole resistance in A. fumigatus, dissecting the intricate genotype-phenotype relationships, spotlighting emerging non-Cyp51A pathways and outlining future strategies to enhance the detection and clinical management of antifungal resistance.
Insights
Aspergillus fumigatus drug resistance threatens antifungal therapy. This review details complex genotype-phenotype links and emerging non-Cyp51A resistance pathways to guide future strategies.
Area of Science:
- Medical Mycology
- Antimicrobial Resistance
- Molecular Biology
Background:
- Aspergillus fumigatus is a critical threat causing invasive fungal disease.
- Triazole antifungals are essential but face rising drug resistance.
- Cyp51A mutations are common resistance drivers, forming specific genotypes.
Purpose of the Study:
- To review current knowledge on azole resistance in Aspergillus fumigatus.
- To dissect complex genotype-phenotype relationships in Cyp51A-mediated resistance.
- To highlight emerging resistance mechanisms independent of Cyp51A.
Main Methods:
- Literature review of studies on Aspergillus fumigatus azole resistance.
- Analysis of genotype-phenotype correlations in clinical isolates.
- Examination of novel resistance mechanisms beyond Cyp51A.
Main Results:
- Cyp51A genotype-phenotype correlations are complex and not always predictable.
- Mutational hotspots in Cyp51A (G54, M220, G448) exhibit varied resistance.
- Non-Cyp51A resistance mechanisms are increasingly identified.
Conclusions:
- Understanding intricate genotype-phenotype relationships is crucial for managing Aspergillus fumigatus resistance.
- Emerging non-Cyp51A resistance pathways require further investigation.
- Enhanced detection and clinical management strategies are needed to combat antifungal resistance.
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