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. 2007 Nov;51(11):4174-6.
doi: 10.1128/AAC.00917-07. Epub 2007 Aug 27.

A Ser678Pro substitution in Fks1p confers resistance to echinocandin drugs in Aspergillus fumigatus

Eleusa Maria F Rocha  1 , Guillermo Garcia-Effron, Steven Park, David S Perlin
Affiliations

A Ser678Pro substitution in Fks1p confers resistance to echinocandin drugs in Aspergillus fumigatus

Eleusa Maria F Rocha et al. Antimicrob Agents Chemother. 2007 Nov.

Abstract

An S678P substitution in Fks1p, the major subunit of glucan synthase, was sufficient to confer echinocandin resistance in Aspergillus fumigatus. The equivalent mutation in Candida spp. has been implicated in echinocandin resistance. This work demonstrates that modification of Fks1p is a conserved mechanism for echinocandin resistance in pathogenic fungi.

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Figures

FIG. 1.
FIG. 1.
Amino acid sequence alignment of Fks1p containing “hot-spot 1” regions from five fungal species: Saccharomyces cerevisiae (Sc), Candida glabrata (Cg), Candida albicans (Ca), Aspergillus nidulans (An), and Aspergillus fumigatus (Af). The highly conserved Ser locus is shaded.
FIG. 2.
FIG. 2.
CSF-sensitive and -resistant isolates of A. fumigatus. (A) Growth of strains EMFR-S678P (mutant) and KU80Δ (wild type) on AM3 with 10.0 μg/ml of CSF plus pyrimidine. (B) Growth of EMFR-S678P/WT containing plasmid-expressed fks1(S678P) (top set). EMFR-FKS1-Restored isolates 1 to 4 with restored sensitivity to echinocandin following loss of plasmid (bottom set). Strains were grown for 72 h at 37°C on AM3 with 10.0 μg/ml of CSF.
FIG. 3.
FIG. 3.
Echinocandin inhibition profiles of enriched GS complexes from the wild type (triangles), EMFR-S678P (circles), and EMFR-FKS1-Restored (squares). The enzymes were evaluated with CSF (A), ANF (B), and MCF (C). The mixed inhibition profile to CSF for GS from EMFR-S678P/WT is also shown (D). Relative GS activities shown in all panels were assessed by the incorporation of [3H]glucose into the radiolabeled product.
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