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Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata.

Publication ,  Journal Article
Singh-Babak, SD; Babak, T; Diezmann, S; Hill, JA; Xie, JL; Chen, Y-L; Poutanen, SM; Rennie, RP; Heitman, J; Cowen, LE
Published in: PLoS Pathog
2012

The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential.

Duke Scholars

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Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

2012

Volume

8

Issue

5

Start / End Page

e1002718

Location

United States

Related Subject Headings

  • Virology
  • Sequence Analysis, DNA
  • Polymorphism, Genetic
  • Middle Aged
  • Microbial Sensitivity Tests
  • Lipopeptides
  • Humans
  • HSP90 Heat-Shock Proteins
  • Glucosyltransferases
  • Genome, Fungal
 

Citation

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ICMJE
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Singh-Babak, S. D., Babak, T., Diezmann, S., Hill, J. A., Xie, J. L., Chen, Y.-L., … Cowen, L. E. (2012). Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog, 8(5), e1002718. https://doi.org/10.1371/journal.ppat.1002718
Singh-Babak, Sheena D., Tomas Babak, Stephanie Diezmann, Jessica A. Hill, Jinglin Lucy Xie, Ying-Lien Chen, Susan M. Poutanen, Robert P. Rennie, Joseph Heitman, and Leah E. Cowen. “Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata.PLoS Pathog 8, no. 5 (2012): e1002718. https://doi.org/10.1371/journal.ppat.1002718.
Singh-Babak SD, Babak T, Diezmann S, Hill JA, Xie JL, Chen Y-L, et al. Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog. 2012;8(5):e1002718.
Singh-Babak, Sheena D., et al. “Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata.PLoS Pathog, vol. 8, no. 5, 2012, p. e1002718. Pubmed, doi:10.1371/journal.ppat.1002718.
Singh-Babak SD, Babak T, Diezmann S, Hill JA, Xie JL, Chen Y-L, Poutanen SM, Rennie RP, Heitman J, Cowen LE. Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog. 2012;8(5):e1002718.

Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

2012

Volume

8

Issue

5

Start / End Page

e1002718

Location

United States

Related Subject Headings

  • Virology
  • Sequence Analysis, DNA
  • Polymorphism, Genetic
  • Middle Aged
  • Microbial Sensitivity Tests
  • Lipopeptides
  • Humans
  • HSP90 Heat-Shock Proteins
  • Glucosyltransferases
  • Genome, Fungal