Yeast species-specific, differential inhibition of β-1,3-glucan synthesis by poacic acid and caspofungin

Keunsook K. Lee, Karen Kubo, Jehan Abdelmoneim Abdelaziz, Iain Cunningham, Alessandra de Silva Dantas, Xiaolin Chen, Hiroki Okada, Yoshikazu Ohya, Neil A.R. Gow (Corresponding Author)

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Abstract

The rise of widespread antifungal resistance fuels the need to explore new classes of inhibitory molecules as potential novel inhibitors. Recently a plant natural product poacic acid (PA) was shown to inhibit β-1,3-glucan synthesis, and to have antifungal activity against a range of plant pathogens and against Saccharomyces cerevisiae. As with the echinocandins, such as caspofungin, PA targets the synthesis of cell wall β-1,3-glucan and has potential utility in the treatment of medically important fungi. However, the antifungal activity of PA against human pathogenic Candida species has not been explored and the precise mode of action of this compound is not understood. Here, we show that PA sensitivity is regulated by the calcineurin pathway and that susceptibility to PA varied significantly between Candida species, but did not correlate with in vitro β-glucan synthase activity, cell wall β-glucan content or the sensitivity of the species to caspofungin. Strains with point mutations (S645Y or S645P) in the hotspot1 region of the β-1,3-glucan synthase subunit Fks1, had decreased sensitivity to caspofungin but increased sensitivity to PA. C. guilliermondii, C. orthopsilosis, and C. parapsilosis were more sensitive to PA than C. albicans, C. dubliniensis, C. tropicalis, and C. glabrata. These observations suggest that there are significant differences in the mode of action of PA and caspofungin and that PA or PA analogues are not likely to have broad spectrum activity in the treatment of Candida infections.
Original languageEnglish
Pages (from-to)12-25
Number of pages14
JournalThe Cell Surface
Volume3
Early online date26 Sep 2018
DOIs
Publication statusPublished - Sep 2018

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caspofungin
Glucans
Yeasts
Candida
Cell Wall
poacic acid
Echinocandins
Calcineurin

Keywords

  • Antifungal agents
  • Glucan synthesis
  • Fks1
  • Fungal cell wall
  • species

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Yeast species-specific, differential inhibition of β-1,3-glucan synthesis by poacic acid and caspofungin. / Lee, Keunsook K.; Kubo, Karen; Abdelaziz, Jehan Abdelmoneim; Cunningham, Iain; de Silva Dantas, Alessandra; Chen, Xiaolin; Okada, Hiroki; Ohya, Yoshikazu; Gow, Neil A.R. (Corresponding Author).

In: The Cell Surface, Vol. 3, 09.2018, p. 12-25.

Research output: Contribution to journalArticle

Lee, KK, Kubo, K, Abdelaziz, JA, Cunningham, I, de Silva Dantas, A, Chen, X, Okada, H, Ohya, Y & Gow, NAR 2018, 'Yeast species-specific, differential inhibition of β-1,3-glucan synthesis by poacic acid and caspofungin', The Cell Surface, vol. 3, pp. 12-25. https://doi.org/10.1016/j.tcsw.2018.09.001
Lee, Keunsook K. ; Kubo, Karen ; Abdelaziz, Jehan Abdelmoneim ; Cunningham, Iain ; de Silva Dantas, Alessandra ; Chen, Xiaolin ; Okada, Hiroki ; Ohya, Yoshikazu ; Gow, Neil A.R. / Yeast species-specific, differential inhibition of β-1,3-glucan synthesis by poacic acid and caspofungin. In: The Cell Surface. 2018 ; Vol. 3. pp. 12-25.
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abstract = "The rise of widespread antifungal resistance fuels the need to explore new classes of inhibitory molecules as potential novel inhibitors. Recently a plant natural product poacic acid (PA) was shown to inhibit β-1,3-glucan synthesis, and to have antifungal activity against a range of plant pathogens and against Saccharomyces cerevisiae. As with the echinocandins, such as caspofungin, PA targets the synthesis of cell wall β-1,3-glucan and has potential utility in the treatment of medically important fungi. However, the antifungal activity of PA against human pathogenic Candida species has not been explored and the precise mode of action of this compound is not understood. Here, we show that PA sensitivity is regulated by the calcineurin pathway and that susceptibility to PA varied significantly between Candida species, but did not correlate with in vitro β-glucan synthase activity, cell wall β-glucan content or the sensitivity of the species to caspofungin. Strains with point mutations (S645Y or S645P) in the hotspot1 region of the β-1,3-glucan synthase subunit Fks1, had decreased sensitivity to caspofungin but increased sensitivity to PA. C. guilliermondii, C. orthopsilosis, and C. parapsilosis were more sensitive to PA than C. albicans, C. dubliniensis, C. tropicalis, and C. glabrata. These observations suggest that there are significant differences in the mode of action of PA and caspofungin and that PA or PA analogues are not likely to have broad spectrum activity in the treatment of Candida infections.",
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author = "Lee, {Keunsook K.} and Karen Kubo and Abdelaziz, {Jehan Abdelmoneim} and Iain Cunningham and {de Silva Dantas}, Alessandra and Xiaolin Chen and Hiroki Okada and Yoshikazu Ohya and Gow, {Neil A.R.}",
note = "We sincerely thank Jeff Piotrowski and John Ralph for providing poacic acid, and David Perlin for providing C. glabrata fks1Δ and fks2Δ mutant strains and clinical isolates (DPL series) for this study. We thank Carol Munro, Sam Miller and Louise Walker for helpful discussions; and Raif Yuecel, Attila Bebes, and Linda Duncan in the Iain Fraser Cytometry Centre (IFCC) for FACS, and Kevin MacKenzie, Debbie Wilkinson, Gillian Milne, and Lucy Wright for microscopy at the University of Aberdeen core facilities. This work was supported by the Wellcome Trust (101873, 086827, 075470, & 200208) and MRC Centre for Medical Mycology (N006364/1), and Grants-in-Aid for Scientific Research from the Ministry of Education Culture, Sports, Science and Technology, Japan (24370002 and 15H04402 to Y.O.).",
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N1 - We sincerely thank Jeff Piotrowski and John Ralph for providing poacic acid, and David Perlin for providing C. glabrata fks1Δ and fks2Δ mutant strains and clinical isolates (DPL series) for this study. We thank Carol Munro, Sam Miller and Louise Walker for helpful discussions; and Raif Yuecel, Attila Bebes, and Linda Duncan in the Iain Fraser Cytometry Centre (IFCC) for FACS, and Kevin MacKenzie, Debbie Wilkinson, Gillian Milne, and Lucy Wright for microscopy at the University of Aberdeen core facilities. This work was supported by the Wellcome Trust (101873, 086827, 075470, & 200208) and MRC Centre for Medical Mycology (N006364/1), and Grants-in-Aid for Scientific Research from the Ministry of Education Culture, Sports, Science and Technology, Japan (24370002 and 15H04402 to Y.O.).

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N2 - The rise of widespread antifungal resistance fuels the need to explore new classes of inhibitory molecules as potential novel inhibitors. Recently a plant natural product poacic acid (PA) was shown to inhibit β-1,3-glucan synthesis, and to have antifungal activity against a range of plant pathogens and against Saccharomyces cerevisiae. As with the echinocandins, such as caspofungin, PA targets the synthesis of cell wall β-1,3-glucan and has potential utility in the treatment of medically important fungi. However, the antifungal activity of PA against human pathogenic Candida species has not been explored and the precise mode of action of this compound is not understood. Here, we show that PA sensitivity is regulated by the calcineurin pathway and that susceptibility to PA varied significantly between Candida species, but did not correlate with in vitro β-glucan synthase activity, cell wall β-glucan content or the sensitivity of the species to caspofungin. Strains with point mutations (S645Y or S645P) in the hotspot1 region of the β-1,3-glucan synthase subunit Fks1, had decreased sensitivity to caspofungin but increased sensitivity to PA. C. guilliermondii, C. orthopsilosis, and C. parapsilosis were more sensitive to PA than C. albicans, C. dubliniensis, C. tropicalis, and C. glabrata. These observations suggest that there are significant differences in the mode of action of PA and caspofungin and that PA or PA analogues are not likely to have broad spectrum activity in the treatment of Candida infections.

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