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Antimicrobial Agents and Chemotherapy, November 2001, p. 3162-3170, Vol. 45, No. 11
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

M. Cristina Cruz,1 Alan L. Goldstein,2 Jill Blankenship,1 Maurizio Del Poeta,3,4 John R. Perfect,2,5 John H. McCusker,1,2 Youssef L. Bennani,6 Maria E. Cardenas,1 and Joseph Heitman1,2,5,7,*

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.

* 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.

Antimicrobial Agents and Chemotherapy, November 2001, p. 3162-3170, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3162-3170.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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