Genotype–Phenotype Relationships in Azole-Resistant Aspergillus: Two Sides of the Same Coin

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.