PMC

Cyclic hexapetides are best differentiated by their aliphatic tails (circled).

Transmembrane segments deduced from analysis of amino acid relative hydrophobicity.

Specific mutations in referred clinical isolates (n = 88) are shown for hot spot one mutations in FKS1 for C. albicans and both FKS1 and FKS2 for C. glabrata.

Cells were grown for 18 h in Roswell Park Memorial Institute (RPMI) medium in the (A) absence or (B) presence of caspofungin at 0.5 mg/ml and visualized by light microscopy (100×).

Glucan synthases with characteristic hot spot one amino acid substitutions were isolated and inhibition of activity (IC₅₀) by each of the echinocandin drugs was determined, as described by Park et al. [].

A composite of Candida spp. in reference library (n = 55) containing WT and FKS mutations were plotted as a function of IC₅₀ and MIC for each of the echinocandin drugs, as shown. The original CLSI breakpoint of ≤2 µg/ml (solid line) fails to capture a significant number of FKS mutants resulting in treatment failure, especially for micafungin and anidulafungin. The new proposed breakpoint (broken line) of ≤0.25–0.5 µg/ml is more inclusive of all FKS mutants. The WT ECR represents Candida spp. (e.g., Candida parapsilosis) with inherent elevated MIC levels.
CLSI: Clinical Laboratory Standards Institute; ECR: Echinocandin resistance; WT: Wild-type.
Partially adapted with permission from [,].