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Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance.

ABSTRACT: The identification of FKS1 mutations in Candida albicans associated with echinocandin resistance has raised concerns over the spread of drug-resistant strains. We studied the impact of fks1 mutations on C. albicans virulence and fitness. Compared with wild-type strains for FKS1, echinocandin-resistant C. albicans strains with homozygous fks1 hot-spot mutations had reduced maximum catalytic capacity of their glucan synthase complexes and thicker cell walls attributable to increased cell wall chitin content. The fks1 mutants with the highest chitin contents had reduced growth rates and impaired filamentation capacities. Fks1 mutants were hypovirulent in fly and mouse models of candidiasis, and this phenotype correlated with the cell wall chitin content. In addition, we observed reduced fitness of echinocandin-resistant C. albicans in competitive mixed infection models. We conclude that fks1 mutations that confer echinocandin resistance come at fitness and virulence costs, which may limit their epidemiological and clinical impact.

SUBMITTER: Ben-Ami R

PROVIDER: S-EPMC3144175 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.

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Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance.

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