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Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin.

Publication ,  Journal Article
Cruz, MC; Del Poeta, M; Wang, P; Wenger, R; Zenke, G; Quesniaux, VF; Movva, NR; Perfect, JR; Cardenas, ME; Heitman, J
Published in: Antimicrob Agents Chemother
January 2000

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.

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Published In

Antimicrob Agents Chemother

DOI

ISSN

0066-4804

Publication Date

January 2000

Volume

44

Issue

1

Start / End Page

143 / 149

Location

United States

Related Subject Headings

  • Temperature
  • Peptidylprolyl Isomerase
  • Microbiology
  • Mice, Inbred CBA
  • Mice, Inbred BALB C
  • Mice
  • Immunosuppressive Agents
  • Humans
  • Fluconazole
  • Drug Resistance, Microbial
 

Citation

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Cruz, M. C., Del Poeta, M., Wang, P., Wenger, R., Zenke, G., Quesniaux, V. F., … Heitman, J. (2000). Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin. Antimicrob Agents Chemother, 44(1), 143–149. https://doi.org/10.1128/AAC.44.1.143-149.2000
Cruz, M. C., M. Del Poeta, P. Wang, R. Wenger, G. Zenke, V. F. Quesniaux, N. R. Movva, J. R. Perfect, M. E. Cardenas, and J. Heitman. “Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin.Antimicrob Agents Chemother 44, no. 1 (January 2000): 143–49. https://doi.org/10.1128/AAC.44.1.143-149.2000.
Cruz, M. C., et al. “Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin.Antimicrob Agents Chemother, vol. 44, no. 1, Jan. 2000, pp. 143–49. Pubmed, doi:10.1128/AAC.44.1.143-149.2000.
Cruz MC, Del Poeta M, Wang P, Wenger R, Zenke G, Quesniaux VF, Movva NR, Perfect JR, Cardenas ME, Heitman J. Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin. Antimicrob Agents Chemother. 2000 Jan;44(1):143–149.

Published In

Antimicrob Agents Chemother

DOI

ISSN

0066-4804

Publication Date

January 2000

Volume

44

Issue

1

Start / End Page

143 / 149

Location

United States

Related Subject Headings

  • Temperature
  • Peptidylprolyl Isomerase
  • Microbiology
  • Mice, Inbred CBA
  • Mice, Inbred BALB C
  • Mice
  • Immunosuppressive Agents
  • Humans
  • Fluconazole
  • Drug Resistance, Microbial