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The immunosuppressant FK506 and its nonimmunosuppressive analog L-685,818 are toxic to Cryptococcus neoformans by inhibition of a common target protein.

Publication ,  Journal Article
Odom, A; Del Poeta, M; Perfect, J; Heitman, J
Published in: Antimicrob Agents Chemother
January 1997

The immunosuppressant FK506 (tacrolimus) is an antifungal natural product macrolide that suppresses the immune system by blocking T-cell activation. In complex with the intracellular protein FKBP12, FK506 inhibits calcineurin, a Ca(2+)-calmodulin-dependent serine-threonine protein phosphatase. We recently reported that growth of the opportunistic fungal pathogen Cryptococcus neoformans is resistant to FK506 at 24 degrees C but sensitive at 37 degrees C and that calcineurin, the target of FKBP12-FK506, is required for growth at 37 degrees C in vitro and pathogenicity in vivo. These findings identify calcineurin as a potential antifungal drug target. In previous studies the calcineurin inhibitor cyclosporin A (CsA) was effective against murine pulmonary infections but exacerbated cryptococcal meningitis in rabbits and mice, likely because CsA does not cross the blood-brain barrier. Although we find that FK506 penetrates the CNS, FK506 also exacerbates cryptococcal meningitis in rabbits. Thus, FK506 immunosuppression outweighs antifungal action in vivo. Like FK506, the nonimmunosuppressive FK506 analog L-685,818 is toxic to C. neoformans in vitro at 37 degrees C but not at 24 degrees C, and FK506-resistant mutants are resistant to L-685,818, indicating a similar mechanism of action. Fluconazole-resistant C. neoformans clinical isolates were also found to be susceptible to both FK506 and L-685,818. Our findings identify calcineurin as a novel antifungal drug target and suggest the nonimmunosuppressive FK506 analog L-685,818 or other congeners warrant further consideration as antifungal drugs for C. neoformans.

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Published In

Antimicrob Agents Chemother

DOI

ISSN

0066-4804

Publication Date

January 1997

Volume

41

Issue

1

Start / End Page

156 / 161

Location

United States

Related Subject Headings

  • Tacrolimus Binding Proteins
  • Tacrolimus
  • Rabbits
  • Protein Binding
  • Phosphoprotein Phosphatases
  • Microbiology
  • Meningitis, Cryptococcal
  • Immunosuppressive Agents
  • Immunosuppression Therapy
  • Heat-Shock Proteins
 

Citation

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Odom, A., Del Poeta, M., Perfect, J., & Heitman, J. (1997). The immunosuppressant FK506 and its nonimmunosuppressive analog L-685,818 are toxic to Cryptococcus neoformans by inhibition of a common target protein. Antimicrob Agents Chemother, 41(1), 156–161. https://doi.org/10.1128/AAC.41.1.156
Odom, A., M. Del Poeta, J. Perfect, and J. Heitman. “The immunosuppressant FK506 and its nonimmunosuppressive analog L-685,818 are toxic to Cryptococcus neoformans by inhibition of a common target protein.Antimicrob Agents Chemother 41, no. 1 (January 1997): 156–61. https://doi.org/10.1128/AAC.41.1.156.
Odom, A., et al. “The immunosuppressant FK506 and its nonimmunosuppressive analog L-685,818 are toxic to Cryptococcus neoformans by inhibition of a common target protein.Antimicrob Agents Chemother, vol. 41, no. 1, Jan. 1997, pp. 156–61. Pubmed, doi:10.1128/AAC.41.1.156.

Published In

Antimicrob Agents Chemother

DOI

ISSN

0066-4804

Publication Date

January 1997

Volume

41

Issue

1

Start / End Page

156 / 161

Location

United States

Related Subject Headings

  • Tacrolimus Binding Proteins
  • Tacrolimus
  • Rabbits
  • Protein Binding
  • Phosphoprotein Phosphatases
  • Microbiology
  • Meningitis, Cryptococcal
  • Immunosuppressive Agents
  • Immunosuppression Therapy
  • Heat-Shock Proteins