Open AccessImmunosuppressive and Nonimmunosuppressive Cyclosporine Analogs Are Toxic to the Opportunistic Fungal Pathogen Cryptococcus neoformans via Cyclophilin-Dependent Inhibition of Calcineurin
Author(s) -
Maricel Dela Cruz,
Maurizio Del Poeta,
Ping Wang,
R. Wenger,
Gerhard Zenke,
Valérie Quesniaux,
N. Rao Movva,
John R. Perfect,
María E. Cárdenas,
Joseph Heitman
Publication year - 2000
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.44.1.143-149.2000
Subject(s) - cryptococcus neoformans , calcineurin , cyclophilin , biology , microbiology and biotechnology , antifungal drug , peptidylprolyl isomerase , in vitro , cryptococcus , cryptococcosis , antimicrobial , biochemistry , antifungal , enzyme , transplantation , medicine , isomerase , surgery , gene
Cyclosporine (CsA) is an immunosuppressive and antimicrobial drug which, in complex with cyclophilin A, inhibits the protein phosphatase calcineurin. We recently found thatCryptococcus 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 againstC. 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, (γ-OH) MeLeu4 -Cs (211-810) and D-Sar (α-SMe)3 Val2 -DH-Cs (209-825), which are also toxic toC. neoformans were identified. These CsA analogs inhibitC. 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.