Interaction of Azole Compounds with DOPC and DOPC/Ergosterol Bilayers by Spin Probe EPR Spectroscopy: Implications for Antifungal Activity

Cicogna, Francesca; Pinzino, Calogero; Castellano, Sabrina; Porta, Amalia; Forte, Claudia; Calucci, Lucia

doi:10.1021/jp406776x

Cited by 3 publications

(1 citation statement)

References 61 publications

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“…In fungi, the main sterol ergosterol has important roles in controlling membrane fluidity 55,56 and supporting the activity of PM enzymes 57 . Consequently, depletion of ergosterol is widely thought to compromise the integrity of the PM 14,15 , and it was suggested that this underpins the fungicidal activity of certain azole compounds 58 . In this study, we use a fluorescent PM syntaxin GFP-Sso1 24 and show reduces membrane fluidity in azoletreated Z. tritici cells, a result that is consistent with findings in C. glabrata 59 .…”

Section: Discussionmentioning

confidence: 99%

Azoles activate type I and type II programmed cell death pathways in crop pathogenic fungi

Schuster,

Kilaru,

Steinberg

2024

Nat Commun

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Triazoles are widely used to control pathogenic fungi. They inhibit the ergosterol biosynthetic pathway, but the precise mechanisms leading to fungicidal activities in many fungal pathogens are poorly understood. Here, we elucidate the mode of action of epoxiconazole and metconazole in the wheat pathogen Zymoseptoria tritici and the rice blast fungus Magnaporthe oryzae. We show that both azoles have fungicidal activity and reduce fluidity, but not integrity, of the plasma membrane. This impairs localisation of Cdc15-like F-BAR proteins, resulting in defective actin ring assembly and incomplete septation. However, mutant studies and pharmacological experiments in vitro and in planta show that azole lethality is due to a combination of reactive oxygen species-induced apoptosis and macroautophagy. Simultaneous inhibition of both programmed cell death pathways abolishes azole-induced cell death. Other classes of ergosterol biosynthesis inhibitors also induce apoptosis and macroautophagy, suggesting that activation of these two cell death pathways is a hallmark of ergosterol synthesis-targeting fungicides. This knowledge will inform future crop protection strategies.

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Section: Discussionmentioning

confidence: 99%

Azoles activate type I and type II programmed cell death pathways in crop pathogenic fungi

Schuster,

Kilaru,

Steinberg

2024

Nat Commun

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Interaction of the antifungal ketoconazole and its diphenylphosphine derivatives with lipid bilayers: Insights into their antifungal action

Bento-Oliveira,

Starosta,

de Almeida

2024

Archives of Biochemistry and Biophysics

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Effects of azole treatments on the physical properties of Candida albicans plasma membrane: A spin probe EPR study

Sgherri

Porta

Castellano

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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EPR spectroscopy was applied to investigate the effects of the treatment of Candida albicans cells with fluconazole (FLC) and two newly synthesized azoles (CPA18 and CPA109), in a concentration not altering yeast morphology, on the lipid organization and dynamics of the plasma membrane. Measurements were performed in the temperature range between 0°C and 40°C using 5-doxyl- (5-DSA) and 16-doxyl- (16-DSA) stearic acids as spin probes. 5-DSA spectra were typical of lipids in a highly ordered environment, whereas 16-DSA spectra consisted of two comparable components, one corresponding to a fluid bulk lipid domain in the membrane and the other to highly ordered and motionally restricted lipids interacting with integral membrane proteins. A line shape analysis allowed the relative proportion and the orientational order and dynamic parameters of the spin probes in the different environments to be determined. Smaller order parameters, corresponding to a looser lipid packing, were found for the treated samples with respect to the control one in the region close to the membrane surface probed by 5-DSA. On the other hand, data on 16-DSA indicated that azole treatments hamper the formation of ordered lipid domains hosting integral proteins and/or lead to a decrease in integral protein content in the membrane. The observed effects are mainly ascribable to the inhibition of ergosterol biosynthesis by the antifungal agents, although a direct interaction of the CPA compounds with the membrane bilayer in the region close to the lipid polar head groups cannot be excluded.

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Interaction of Azole Compounds with DOPC and DOPC/Ergosterol Bilayers by Spin Probe EPR Spectroscopy: Implications for Antifungal Activity

Cited by 3 publications

References 61 publications

Azoles activate type I and type II programmed cell death pathways in crop pathogenic fungi

Azoles activate type I and type II programmed cell death pathways in crop pathogenic fungi

Interaction of the antifungal ketoconazole and its diphenylphosphine derivatives with lipid bilayers: Insights into their antifungal action

Effects of azole treatments on the physical properties of Candida albicans plasma membrane: A spin probe EPR study

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