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Antimicrobial Agents and Chemotherapy, January 2000, p. 143-149, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Immunosuppressive and Nonimmunosuppressive Cyclosporine Analogs Are Toxic to the Opportunistic Fungal Pathogen Cryptococcus neoformans via Cyclophilin-Dependent Inhibition of Calcineurin

M. Cristina Cruz,1 Maurizio Del Poeta,2,3 Ping Wang,1 Roland Wenger,4 Gerhard Zenke,4 Valerie F. J. Quesniaux,4 N. Rao Movva,4 John R. Perfect,2,5 Maria E. Cardenas,1 and Joseph Heitman1,2,5,6,7,*

Departments of Genetics,1 Pharmacology and Cancer Biology,6 Microbiology,5 and Medicine,2 Duke University Medical Center and Howard Hughes Medical Institute,7 Durham, North Carolina 27710; Institute of Infectious Diseases and Public Health, University of Ancona, Ancona, Italy3; and Novartis, Basel CH-4002, Switzerland4

Received 24 June 1999/Returned for modification 18 August 1999/Accepted 25 October 1999

Cyclosporine (CsA) is an immunosuppressive and antimicrobial drug which, in complex with cyclophilin A, inhibits the protein phosphatase calcineurin. We recently found that Cryptococcus neoformans growth is resistant to CsA at 24°C but sensitive at 37°C and that calcineurin is required for growth at 37°C and pathogenicity. Here CsA analogs were screened for toxicity against C. neoformans in vitro. In most cases, antifungal activity was correlated with cyclophilin A binding in vitro and inhibition of the mixed-lymphocyte reaction and interleukin 2 production in cell culture. Two unusual nonimmunosuppressive CsA derivatives, (gamma -OH) MeLeu4-Cs (211-810) and D-Sar (alpha -SMe)3 Val2-DH-Cs (209-825), which are also toxic to C. neoformans were identified. These CsA analogs inhibit C. neoformans via fungal cyclophilin A and calcineurin homologs. Our findings identify calcineurin as a novel antifungal drug target and suggest nonimmunosuppressive CsA analogs warrant investigation as 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, January 2000, p. 143-149, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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