Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR

M. C. Cruz, A. L. Goldstein, Jill R Blankenship, M. Del Poeta, J. R. Perfect, J. H. McCusker, Y. L. Bennani, M. E. Cardenas, J. Heitman

Research output: Contribution to journalArticle

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Abstract

Candida albicans and Cryptococcus neoformans cause both superficial and disseminated infections in humans. Current antifungal therapies for deep-seated infections are limited to amphotericin B, flucytosine, and azoles. A limitation is that commonly used azoles are fungistatic in vitro and in vivo. Our studies address the mechanisms of antifungal activity of the immunosuppressive drug rapamycin (sirolimus) and its analogs with decreased immunosuppressive activity. C. albicans rbp1/rbp1 mutant strains lacking a homolog of the FK506-rapamycin target protein FKBP12 were found to be viable and resistant to rapamycin and its analogs. Rapamycin and analogs promoted FKBP12 binding to the wild-type Tor1 kinase but not to a rapamycin-resistant Tor1 mutant kinase (S1972R). FKBP12 and TOR mutations conferred resistance to rapamycin and its analogs in C. albicans, C. neoformans, and Saccharomyces cerevisiae. Our findings demonstrate the antifungal activity of rapamycin and rapamycin analogs is mediated via conserved complexes with FKBP12 and Tor kinase homologs in divergent yeasts. Taken together with our observations that rapamycin and its analogs are fungicidal and that spontaneous drug resistance occurs at a low rate, these mechanistic findings support continued investigation of rapamycin analogs as novel antifungal agents.

Original languageEnglish (US)
Pages (from-to)3162-3170
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume45
Issue number11
DOIs
StatePublished - Nov 1 2001

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Tacrolimus Binding Protein 1A
Cryptococcus neoformans
Poisons
Sirolimus
Immunosuppressive Agents
Candida albicans
Azoles
Phosphotransferases
TOR Serine-Threonine Kinases
Flucytosine
Antifungal Agents
Tacrolimus
Amphotericin B
Infection
Drug Resistance
Saccharomyces cerevisiae
Yeasts

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR. / Cruz, M. C.; Goldstein, A. L.; Blankenship, Jill R; Del Poeta, M.; Perfect, J. R.; McCusker, J. H.; Bennani, Y. L.; Cardenas, M. E.; Heitman, J.

In: Antimicrobial Agents and Chemotherapy, Vol. 45, No. 11, 01.11.2001, p. 3162-3170.

Research output: Contribution to journalArticle

Cruz, M. C. ; Goldstein, A. L. ; Blankenship, Jill R ; Del Poeta, M. ; Perfect, J. R. ; McCusker, J. H. ; Bennani, Y. L. ; Cardenas, M. E. ; Heitman, J. / Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR. In: Antimicrobial Agents and Chemotherapy. 2001 ; Vol. 45, No. 11. pp. 3162-3170.
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