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

Research output: Contribution to journalArticle

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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 1

Fingerprint

Tacrolimus
Pharmaceutical Preparations
Immunosuppressive Agents
Calcineurin
Cryptococcus neoformans
Fluconazole
In Vitro Techniques
Fungi
Tacrolimus Binding Protein 1A
NFATC Transcription Factors
Cryptococcosis
Aspergillus fumigatus
Candida albicans
Allografts
Virulence
Mammals
Carrier Proteins

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Lee, Yeonseon ; Lee, Kyung Tae ; Lee, Soo Jung ; Beom, Ji Yoon ; Hwangbo, Areum ; Jung, Jin A. ; Song, Myoung Chong ; Yoo, Young Ji ; Kang, Sang Hyeon ; Averette, Anna F. ; Heitman, Joseph ; Yoon, Yeo Joon ; Cheong, Eunji ; Bahn, Yong-Sun. / In vitro and in vivo assessment of FK506 analogs as novel antifungal drug candidates. In: Antimicrobial Agents and Chemotherapy. 2018 ; Vol. 62, No. 11.
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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.",
author = "Yeonseon Lee and Lee, {Kyung Tae} and Lee, {Soo Jung} and Beom, {Ji Yoon} and Areum Hwangbo and Jung, {Jin A.} and Song, {Myoung Chong} and Yoo, {Young Ji} and Kang, {Sang Hyeon} and Averette, {Anna F.} and Joseph Heitman and Yoon, {Yeo Joon} and Eunji Cheong and Yong-Sun Bahn",
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Lee, Y, Lee, KT, Lee, SJ, Beom, JY, Hwangbo, A, Jung, JA, Song, MC, Yoo, YJ, Kang, SH, Averette, AF, Heitman, J, Yoon, YJ, Cheong, E & Bahn, Y-S 2018, 'In vitro and in vivo assessment of FK506 analogs as novel antifungal drug candidates', Antimicrobial Agents and Chemotherapy, vol. 62, no. 11, e01627-18. https://doi.org/10.1128/AAC.01627-18

In vitro and in vivo assessment of FK506 analogs as novel antifungal drug candidates. / Lee, Yeonseon; Lee, Kyung Tae; Lee, Soo Jung; Beom, Ji Yoon; Hwangbo, Areum; Jung, Jin A.; Song, Myoung Chong; Yoo, Young Ji; Kang, Sang Hyeon; Averette, Anna F.; Heitman, Joseph; Yoon, Yeo Joon; Cheong, Eunji; Bahn, Yong-Sun.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 11, e01627-18, 01.11.2018.

Research output: Contribution to journalArticle

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T1 - In vitro and in vivo assessment of FK506 analogs as novel antifungal drug candidates

AU - Lee, Yeonseon

AU - Lee, Kyung Tae

AU - Lee, Soo Jung

AU - Beom, Ji Yoon

AU - Hwangbo, Areum

AU - Jung, Jin A.

AU - Song, Myoung Chong

AU - Yoo, Young Ji

AU - Kang, Sang Hyeon

AU - Averette, Anna F.

AU - Heitman, Joseph

AU - Yoon, Yeo Joon

AU - Cheong, Eunji

AU - Bahn, Yong-Sun

PY - 2018/11/1

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N2 - 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.

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