Modulation of Alternaria infectoria cell wall chitin and glucan synthesis by cell wall synthase inhibitors

Chantal Fernandes, Jorge Anjos, Louise A Walker, Branca M A Silva, Luísa Cortes, Marta Mota, Carol A Munro, Neil A R Gow, Teresa Gonçalves

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The present work reports the effects of caspofungin, a β-1,3-glucan synthase inhibitor, and nikkomycin Z, an inhibitor of chitin synthases, on two strains of Alternaria infectoria, a melanized fungus involved in opportunistic human infections and respiratory allergies. One of the strains tested, IMF006, bore phenotypic traits that conferred advantages in resisting antifungal treatment. First, the resting cell wall chitin content was higher and in response to caspofungin, the chitin level remained constant. In the other strain, IMF001, the chitin content increased upon caspofungin treatment to values similar to basal IMF006 levels. Moreover, upon caspofungin treatment, the FKS1 gene was upregulated in IMF006 and downregulated in IMF001. In addition, the resting β-glucan content was also different in both strains, with higher levels in IMF001 than in IMF006. However, this did not provide any advantage with respect to echinocandin resistance. We identified eight different chitin synthase genes and studied relative gene expression when the fungus was exposed to the antifungals under study. In both strains, exposure to caspofungin and nikkomycin Z led to modulation of the expression of class V and VII chitin synthase genes, suggesting its importance in the robustness of A. infectoria. The pattern of A. infectoria phagocytosis and activation of murine macrophages by spores was not affected by caspofungin. Monotherapy with nikkomycin Z and caspofungin provided only fungistatic inhibition, while a combination of both led to fungal cell lysis, revealing a strong synergistic action between the chitin synthase inhibitor and the β-glucan synthase inhibitor against this fungus.

Original languageEnglish
Pages (from-to)2894-2904
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number5
Early online date10 Mar 2014
DOIs
Publication statusPublished - May 2014

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caspofungin
Alternaria
Chitin
Glucans
Cell Wall
Chitin Synthase
Fungi
Echinocandins
Genes
Macrophage Activation
Opportunistic Infections
Spores
Phagocytosis
Hypersensitivity
Down-Regulation

Cite this

Fernandes, C., Anjos, J., Walker, L. A., Silva, B. M. A., Cortes, L., Mota, M., ... Gonçalves, T. (2014). Modulation of Alternaria infectoria cell wall chitin and glucan synthesis by cell wall synthase inhibitors. Antimicrobial Agents and Chemotherapy, 58(5), 2894-2904. https://doi.org/10.1128/AAC.02647-13

Modulation of Alternaria infectoria cell wall chitin and glucan synthesis by cell wall synthase inhibitors. / Fernandes, Chantal; Anjos, Jorge; Walker, Louise A; Silva, Branca M A; Cortes, Luísa; Mota, Marta; Munro, Carol A; Gow, Neil A R; Gonçalves, Teresa.

In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 5, 05.2014, p. 2894-2904.

Research output: Contribution to journalArticle

Fernandes, Chantal ; Anjos, Jorge ; Walker, Louise A ; Silva, Branca M A ; Cortes, Luísa ; Mota, Marta ; Munro, Carol A ; Gow, Neil A R ; Gonçalves, Teresa. / Modulation of Alternaria infectoria cell wall chitin and glucan synthesis by cell wall synthase inhibitors. In: Antimicrobial Agents and Chemotherapy. 2014 ; Vol. 58, No. 5. pp. 2894-2904.
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abstract = "The present work reports the effects of caspofungin, a β-1,3-glucan synthase inhibitor, and nikkomycin Z, an inhibitor of chitin synthases, on two strains of Alternaria infectoria, a melanized fungus involved in opportunistic human infections and respiratory allergies. One of the strains tested, IMF006, bore phenotypic traits that conferred advantages in resisting antifungal treatment. First, the resting cell wall chitin content was higher and in response to caspofungin, the chitin level remained constant. In the other strain, IMF001, the chitin content increased upon caspofungin treatment to values similar to basal IMF006 levels. Moreover, upon caspofungin treatment, the FKS1 gene was upregulated in IMF006 and downregulated in IMF001. In addition, the resting β-glucan content was also different in both strains, with higher levels in IMF001 than in IMF006. However, this did not provide any advantage with respect to echinocandin resistance. We identified eight different chitin synthase genes and studied relative gene expression when the fungus was exposed to the antifungals under study. In both strains, exposure to caspofungin and nikkomycin Z led to modulation of the expression of class V and VII chitin synthase genes, suggesting its importance in the robustness of A. infectoria. The pattern of A. infectoria phagocytosis and activation of murine macrophages by spores was not affected by caspofungin. Monotherapy with nikkomycin Z and caspofungin provided only fungistatic inhibition, while a combination of both led to fungal cell lysis, revealing a strong synergistic action between the chitin synthase inhibitor and the β-glucan synthase inhibitor against this fungus.",
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note = "Article Accepted Date: 3 March 2014. ACKNOWLEDGMENTS This study was partly supported by a Merck, Sharp & Dohme, Inc., medical school grant (P-1599) and by a project funded by FCT-Funda{\cc}{\~a}o para a Ci{\^e}ncia e Tecnologia (PTDC/SAU-ESA/108636/2008, cofunded by COMPETE and FEDER, and PEst-C/SAU/LA0001/2013-2014). J.A. was the recipient of a postdoctoral fellowship from FCT-Funda{\cc}{\~a}o para a Ci{\^e}ncia e Tecnologia (SFRH/BPD/34419/2006). C.F. is a recipient of a postdoctoral fellowship from FCT-Funda{\cc}{\~a}o para a Ci{\^e}ncia e Tecnologia (SFRH/BPD/63733/2009). B.M.A.S. was a recipient of a research fellowship within the scope of FCT project PTDC/SAU-ESA/108636/2008. N.A.R.G. is supported by the Wellcome Trust (080088, 086827, 075470, and 097377). We acknowledge Frank Odds and N. Empadinhas for helpful and stimulating discussions.",
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N1 - Article Accepted Date: 3 March 2014. ACKNOWLEDGMENTS This study was partly supported by a Merck, Sharp & Dohme, Inc., medical school grant (P-1599) and by a project funded by FCT-Fundação para a Ciência e Tecnologia (PTDC/SAU-ESA/108636/2008, cofunded by COMPETE and FEDER, and PEst-C/SAU/LA0001/2013-2014). J.A. was the recipient of a postdoctoral fellowship from FCT-Fundação para a Ciência e Tecnologia (SFRH/BPD/34419/2006). C.F. is a recipient of a postdoctoral fellowship from FCT-Fundação para a Ciência e Tecnologia (SFRH/BPD/63733/2009). B.M.A.S. was a recipient of a research fellowship within the scope of FCT project PTDC/SAU-ESA/108636/2008. N.A.R.G. is supported by the Wellcome Trust (080088, 086827, 075470, and 097377). We acknowledge Frank Odds and N. Empadinhas for helpful and stimulating discussions.

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N2 - The present work reports the effects of caspofungin, a β-1,3-glucan synthase inhibitor, and nikkomycin Z, an inhibitor of chitin synthases, on two strains of Alternaria infectoria, a melanized fungus involved in opportunistic human infections and respiratory allergies. One of the strains tested, IMF006, bore phenotypic traits that conferred advantages in resisting antifungal treatment. First, the resting cell wall chitin content was higher and in response to caspofungin, the chitin level remained constant. In the other strain, IMF001, the chitin content increased upon caspofungin treatment to values similar to basal IMF006 levels. Moreover, upon caspofungin treatment, the FKS1 gene was upregulated in IMF006 and downregulated in IMF001. In addition, the resting β-glucan content was also different in both strains, with higher levels in IMF001 than in IMF006. However, this did not provide any advantage with respect to echinocandin resistance. We identified eight different chitin synthase genes and studied relative gene expression when the fungus was exposed to the antifungals under study. In both strains, exposure to caspofungin and nikkomycin Z led to modulation of the expression of class V and VII chitin synthase genes, suggesting its importance in the robustness of A. infectoria. The pattern of A. infectoria phagocytosis and activation of murine macrophages by spores was not affected by caspofungin. Monotherapy with nikkomycin Z and caspofungin provided only fungistatic inhibition, while a combination of both led to fungal cell lysis, revealing a strong synergistic action between the chitin synthase inhibitor and the β-glucan synthase inhibitor against this fungus.

AB - The present work reports the effects of caspofungin, a β-1,3-glucan synthase inhibitor, and nikkomycin Z, an inhibitor of chitin synthases, on two strains of Alternaria infectoria, a melanized fungus involved in opportunistic human infections and respiratory allergies. One of the strains tested, IMF006, bore phenotypic traits that conferred advantages in resisting antifungal treatment. First, the resting cell wall chitin content was higher and in response to caspofungin, the chitin level remained constant. In the other strain, IMF001, the chitin content increased upon caspofungin treatment to values similar to basal IMF006 levels. Moreover, upon caspofungin treatment, the FKS1 gene was upregulated in IMF006 and downregulated in IMF001. In addition, the resting β-glucan content was also different in both strains, with higher levels in IMF001 than in IMF006. However, this did not provide any advantage with respect to echinocandin resistance. We identified eight different chitin synthase genes and studied relative gene expression when the fungus was exposed to the antifungals under study. In both strains, exposure to caspofungin and nikkomycin Z led to modulation of the expression of class V and VII chitin synthase genes, suggesting its importance in the robustness of A. infectoria. The pattern of A. infectoria phagocytosis and activation of murine macrophages by spores was not affected by caspofungin. Monotherapy with nikkomycin Z and caspofungin provided only fungistatic inhibition, while a combination of both led to fungal cell lysis, revealing a strong synergistic action between the chitin synthase inhibitor and the β-glucan synthase inhibitor against this fungus.

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DO - 10.1128/AAC.02647-13

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