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Antimicrobial Agents and Chemotherapy, August 2009, p. 3337-3346, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01564-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization{triangledown} ,{dagger}

Kristy Dolan,1 Sara Montgomery,1 Bradley Buchheit,1 Louis DiDone,1 Melanie Wellington,1 and Damian J. Krysan1,2*

Departments of Pediatrics,1 Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York 146422

Received 24 November 2008/ Returned for modification 28 January 2009/ Accepted 25 May 2009

Tamoxifen (TAM), an estrogen receptor antagonist used primarily to treat breast cancer, has well-recognized antifungal properties, but the activity of TAM has not been fully characterized using standardized (i.e., CLSI) in vitro susceptibility testing, nor has it been demonstrated in an in vivo model of fungal infection. In addition, its mechanism of action remains to be clearly defined at the molecular level. Here, we report that TAM displays in vitro activity (MIC, 8 to 64 µg/ml) against pathogenic yeasts (Candida albicans, other Candida spp., and Cryptococcus neoformans). In vivo, 200 mg/kg of body weight per day TAM reduced kidney fungal burden (–1.5 log10 CFU per g tissue; P = 0.008) in a murine model of disseminated candidiasis. TAM is a known inhibitor of mammalian calmodulin, and TAM-treated yeast show phenotypes consistent with decreased calmodulin function, including lysis, decreased new bud formation, disrupted actin polarization, and decreased germ tube formation. The overexpression of calmodulin suppresses TAM toxicity, hypofunctional calmodulin mutants are hypersensitive to TAM, and TAM interferes with the interaction between Myo2p and calmodulin, suggesting that TAM targets calmodulin as part of its mechanism of action. Taken together, these experiments indicate that the further study of compounds related to TAM as antifungal agents is warranted.

* Corresponding author. Mailing address: Departments of Pediatrics and Microbiology and Immunology, University of Rochester Medical Center, Box 850, 601 Elwood Ave., Rochester, NY 14642. Phone: (585) 275-9729. Fax: (585) 273-1104. E-mail: damian_krysan{at}urmc.rochester.edu

{triangledown} Published ahead of print on 1 June 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3337-3346, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01564-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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