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Antimicrobial Agents and Chemotherapy, November 2001, p. 3162-3170, Vol. 45, No. 11
Departments of
Genetics,1
Microbiology,2 Pharmacology and
Cancer Biology,7 and
Medicine,5 The Howard Hughes Medical
Institute, Duke University Medical Center, Durham, North Carolina
27710; Departments of Biochemistry and Molecular
Biology3 and Microbiology and
Immunology,4 Medical University of South
Carolina, Charleston, South Carolina 29425; and Abbott
Laboratories, Abbott Park, Illinois 600646
Received 23 April 2001/Returned for modification 10 July
2001/Accepted 2 August 2001
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.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.11.3162-3170.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Rapamycin and Less Immunosuppressive Analogs Are
Toxic to Candida albicans and Cryptococcus
neoformans via FKBP12-Dependent Inhibition of TOR
*
Corresponding author. Mailing address: Box 3546, 322 CARL Bldg., Research Dr., Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail:
heitm001{at}duke.edu.
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