In vitro and in vivo assessment of FK506 analogs as novel antifungal drug candidates

Yeonseon Lee, Kyung Tae Lee, Soo Jung Lee, Ji Yoon Beom, Areum Hwangbo, Jin A. Jung, Myoung Chong Song, Young Ji Yoo, Sang Hyeon Kang, Anna F. Averette, Joseph Heitman, Yeo Joon Yoon, Eunji Cheong, Yong Sun Bahn

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21 Citations (Scopus)

Abstract

FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human-pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with that of FK506. The four FK506 analogs generally possessed lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus. Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of its in vivo antifungal efficacy in a murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, when it was used in combination with fluconazole, it significantly extended the survival of C. neoformans-infected mice, confirming the synergistic in vivo antifungal efficacy between these two agents.

Original languageEnglish
Article numbere01627-18
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number11
DOIs
Publication statusPublished - 2018 Nov

Bibliographical note

Funding Information:
(N0001720). This work was also supported in part by P01 (P01-AI104533-04) and R01 (R01-AI112595-04) NIH/NIAID grants to J.H., by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) (2016R1A2A1A0500507) to Yeo Joon Yoon, and by the Yonsei University Research Fund (Yonsei Frontier Lab Young Researcher Supporting Program to K.-T.L.) of 2018. We declare that we have no conflicts of interest.

Funding Information:
This work was supported by the General International Collaborative R&D program, funded by the Ministry of Trade, Industry and Energy (MOTIE) of the Republic of Korea (N0001720). This work was also supported in part by P01 (P01-AI104533-04) and R01 (R01-AI112595-04) NIH/NIAID grants to J.H., by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) (2016R1A2A1A0500507) to Yeo Joon Yoon, and by the Yonsei University Research Fund (Yonsei Frontier Lab Young Researcher Supporting Program to K.-T.L.) of 2018.

Funding Information:
This work was supported by the General International Collaborative R&D program, funded by the Ministry of Trade, Industry and Energy (MOTIE) of the Republic of Korea

Publisher Copyright:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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