Echinocandins (caspofungin, micafungin, anidulafungin) are first-line for invasive candidiasis. Their mechanism differs fundamentally from other antifungals. Which statement accurately describes echinocandin resistance in Candida glabrata?

• A C. glabrata develops echinocandin resistance via hotspot mutations in FKS1 and FKS2 genes encoding the β-1,3-glucan synthase catalytic subunit, reducing drug binding affinity ✓
• B C. glabrata develops resistance via mutations in the ergosterol biosynthesis pathway, the same mechanism as azole resistance, which crosslinks with echinocandin target pathways
• C C. glabrata overexpresses CDR1 and CDR2 efflux pumps that export echinocandins before they reach β-glucan synthase
• D C. glabrata switches to a hyphal phenotype when echinocandin is present, and hyphae lack β-1,3-glucan synthase expression

Explanation

Echinocandins inhibit β-1,3-glucan synthase, an enzyme complex encoded by FKS1 and FKS2 genes that synthesises β-glucan in the fungal cell wall. C. glabrata (now reclassified as Nakaseomyces glabrata) is notorious for rapidly developing FKS mutations, particularly in 'hot spot' regions HS1 and HS2 of FKS1/FKS2. These mutations (e.g., S645F in FKS1) reduce the enzyme's affinity for echinocandins 10–1000 fold while maintaining catalytic activity for substrate. C. glabrata has a naturally higher mutation rate and can also combine FKS mutations with azole resistance (via ERG11 upregulation), creating pan-resistant strains — a major clinical problem in haematology units.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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