A patient on fluconazole for systemic candidiasis does not respond after 5 days. MIC testing shows fluconazole MIC of 32 mcg/mL (resistant). The most common molecular mechanism of this acquired azole resistance in Candida albicans is:
- A Mutations in ERG11 (CYP51A1) encoding lanosterol 14-alpha-demethylase, often in the azole-binding pocket, reducing drug-enzyme affinity ✓
- B Overexpression of FKS1 encoding beta-glucan synthase sequestering the drug
- C Acquisition of bacterial-like beta-lactamase genes via horizontal gene transfer
- D Upregulation of UPC2 transcription factor causing ergosterol overproduction that dilutes drug effect
Explanation
Fluconazole resistance in Candida albicans arises through several mechanisms: (1) most commonly, point mutations in ERG11 (encoding the target enzyme lanosterol 14-alpha-demethylase/CYP51A1) — especially at positions Y132, K143, F126, and others — that alter the azole-binding site and reduce drug-enzyme affinity; (2) CDR1/CDR2 efflux pump overexpression (ABC transporters driven by gain-of-function transcription factor TAC1 mutations); (3) MDR1/FLU1 upregulation (MFS efflux transporter); and (4) ERG11 overexpression. FKS1 mutations cause echinocandin resistance, not azole resistance. Bacterial-type horizontal gene transfer of resistance enzymes does not occur for azoles in Candida. UPC2 gain-of-function mutations upregulate ERG11, contributing to resistance, but ERG11 point mutations remain the single most commonly detected mechanism.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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