Aspergillus fumigatus resistance to azole antifungals (voriconazole, itraconazole) most commonly involves which molecular mechanism?

• A Overexpression of efflux pumps encoded by CDR1 and MDR1 genes removing azoles from the fungal cell
• B Mutations in the FKS1 gene encoding beta-1,3-glucan synthase causing azole cross-resistance
• C Methylation of the ERG11 gene promoter in the environment through agricultural azole fungicide exposure
• D Mutations in the cyp51A gene (encoding lanosterol 14-alpha-demethylase), particularly TR34/L98H — a tandem repeat insertion in the promoter combined with a leucine-to-histidine substitution at codon 98 ✓

Explanation

Azole resistance in Aspergillus fumigatus most commonly results from mutations in the cyp51A gene encoding lanosterol 14-alpha-demethylase (the azole target), particularly the TR34/L98H (tandem repeat of 34 bp in the promoter + Leu98His amino acid substitution) environmental resistance mechanism arising from azole fungicide use in agriculture. This specific combination increases cyp51A expression (promoter TR) and reduces azole binding affinity (L98H), conferring pan-azole resistance. CDR1/MDR1 efflux overexpression is the primary mechanism in Candida albicans, not Aspergillus. FKS1 mutations cause echinocandin resistance. ERG11 promoter methylation is not a recognised mechanism in clinical Aspergillus.

Reference: Ananthanarayan & Paniker's Textbook of Microbiology, 11th ed.

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