Echinocandins (caspofungin, micafungin, anidulafungin) inhibit beta-1,3-glucan synthase. Which organism is INTRINSICALLY resistant to echinocandins, and what is the biochemical basis?

• A Candida glabrata — due to FKS2 gene mutations causing acquired resistance
• B Aspergillus fumigatus — due to upregulated CYP51A mutations affecting ergosterol biosynthesis
• C Cryptococcus neoformans — its cell wall contains minimal beta-1,3-glucan; it relies predominantly on a polysaccharide capsule and ergosterol-containing membrane rather than glucan-dependent wall architecture ✓
• D Candida auris — intrinsic resistance due to active drug efflux via CDR1 overexpression

Explanation

Cryptococcus neoformans is intrinsically resistant to echinocandins because its cell wall contains little to no beta-1,3-glucan — the specific target of this drug class. Cryptococcal cell wall architecture is dominated by a thick polysaccharide capsule (glucuronoxylomannan and galactoxylomannan), with the fungal membrane primarily protected by ergosterol. Without a meaningful amount of the target enzyme (beta-1,3-glucan synthase) substrate incorporated into the cell wall, echinocandins have no therapeutic activity. FKS hot-spot mutations causing acquired resistance occur in Candida species (not intrinsic Cryptococcus resistance). Candida auris has complex multi-drug resistance patterns but is not invariably intrinsically echinocandin-resistant.

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

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