TY - JOUR
T1 - Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance
AU - Ben-Ami, Ronen
AU - Garcia-Effron, Guillermo
AU - Lewis, Russell E.
AU - Gamarra, Soledad
AU - Leventakos, Konstantinos
AU - Perlin, David S.
AU - Kontoyiannis, Dimitrios P.
N1 - Funding Information:
Potential conflicts of interest. D. P. K. has received research support and honoraria from Merck, Fujisawa, Enzon, Pfizer, and Schering-Plough. R. E. L. has received research support from Merck, Fujisawa, Pfizer, and Enzon. D. S. P. has received research support from and Pfizer. R. B-A. has received consulting fees and research support from Pfizer. All other authors: no conflicts.
Funding Information:
This work was supported by the U. S. Investigator-Initiated Studies Program of Merck (to D. P. K.), the M. D. Anderson Cancer Center Faculty E. N. Cobb Scholar Award Research Endowment (to D. P. K.), the National Institutes of Health through M. D. Anderson’s Cancer Center Support Grant (CA016672), and National Institutes of Health (AI069397), and Pfizer (to D. S. P.).
PY - 2011/8/15
Y1 - 2011/8/15
N2 - 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.
AB - 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.
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U2 - 10.1093/infdis/jir351
DO - 10.1093/infdis/jir351
M3 - Article
C2 - 21791665
AN - SCOPUS:79960884598
SN - 0022-1899
VL - 204
SP - 626
EP - 635
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 4
ER -