Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin.
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 degrees C but sensitive at 37 degrees C and that calcineurin is required for growth at 37 degrees 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) MeLeu(4)-Cs (211-810) and D-Sar (alpha-SMe)(3) Val(2)-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.
Cruz
M C
MC
Department of Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Del Poeta
M
M
Wang
P
P
Wenger
R
R
Zenke
G
G
Quesniaux
V F
VF
Movva
N R
NR
Perfect
J R
JR
Cardenas
M E
ME
Heitman
J
J
D000818:Animals; D065095:Calcineurin Inhibitors; D003455:Cryptococcus neoformans / Q000187:drug effects*; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D019696:Peptidylprolyl Isomerase / Q000502:physiology*; D013696:Temperature
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D015725:Fluconazole; D019696:Peptidylprolyl Isomerase