The role of oxidative and nitrosative bursts caused by azoles and amphotericin B against the fungal pathogen Cryptococcus gattii

Ferreira, Gabriella Freitas; Baltazar, Ludmila de Matos; Santos, Julliana Ribeiro Alves; Monteiro, Andrea de Souza; Fraga, Lúcia Alves de Oliveira; Stoianoff, Maria Aparecida de Resende; Santos, Danielle Anjos dos

doi:10.1093/jac/dkt114

Cited by 98 publications

(96 citation statements)

References 32 publications

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“…The evaluation of the time-kill kinetics (using concentrations equal to the MIC and 2ϫMIC) and the postantifungal effect (PAFE) (using concentrations equal to the MIC) of itraconazole against the original C. gattii strains and the heteroresistant clones were performed as previously described (10,13).…”

Section: Methodsmentioning

confidence: 99%

“…The amount of ergosterol in the original and heteroresistant L135/03 and L27/01 C. gattii strains following a 1-h treatment with itraconazole was determined using n-heptane (SigmaAldrich). Spectrophotometric readings were taken at 282 nm as described previously (10,17). A calibration curve using an ergosterol standard (Sigma-Aldrich) was constructed and used to calculate the amount of ergosterol in the yeast.…”

Section: Methodsmentioning

confidence: 99%

“…The original and heteroresistant yeast cells from the L135/03 and L27/01 strains were treated with itraconazole for 1 h prior to the tests. 2=,7=-Dichlorofluorescein diacetate (DCFH-DA; Invitrogen, Carlsbad, CA, USA) was used for reactive oxygen species (ROS) quantification, and fluorescence was measured with a fluorometer (Synergy 2 SL luminescence microplate reader; Biotek) (10,17). The products of the lipid peroxidation were measured as thiobarbituric acid-reactive substances (TBARS) (10,17).…”

Section: Methodsmentioning

confidence: 99%

“…2=,7=-Dichlorofluorescein diacetate (DCFH-DA; Invitrogen, Carlsbad, CA, USA) was used for reactive oxygen species (ROS) quantification, and fluorescence was measured with a fluorometer (Synergy 2 SL luminescence microplate reader; Biotek) (10,17). The products of the lipid peroxidation were measured as thiobarbituric acid-reactive substances (TBARS) (10,17). A cell extract of C. gattii cells was obtained for the measurement of superoxide dismutase (SOD) and peroxidase (PER) activities (10,17).…”

Section: Methodsmentioning

confidence: 99%

“…Fluconazole treatment does not result in the formation of free radicals, while itraconazole induces oxidative stress at the beginning of treatment, which triggers the antioxidant enzymatic system (10).…”

mentioning

confidence: 99%

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Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii

Ferreira

Santos

Costa

et al. 2015

Antimicrob Agents Chemother

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cCryptococcus gattii is the main etiological agent of cryptococcosis in immunocompetent individuals. The triazole drug itraconazole is one of the antifungals used to treat patients with cryptococcosis. Heteroresistance is an adaptive mechanism to counteract the stress of increasing drug concentrations, and it can enhance the ability of a microorganism to survive under antifungal pressure. In this study, we evaluated the ability of 11 C. gattii strains to develop itraconazole heteroresistance. Heteroresistant clones were analyzed for drug susceptibility, alterations in cell diameter, capsule properties, and virulence in a murine model. Heteroresistance to itraconazole was intrinsic in all of the strains analyzed, reduced both the capsule size and the cell diameter, induced molecular heterogeneity at the chromosomal level, changed the negatively charged cells, reduced ergosterol content, and improved the antioxidant system. A positive correlation between surface/volume ratio of original cells and the level of heteroresistance to itraconazole (LHI) was observed in addition to a negative correlation between capsule size of heteroresistant clones and LHI. Moreover, heteroresistance to itraconazole increased the engulfment of C. gattii by macrophages and augmented fungal proliferation inside these cells, which probably accounted for the reduced survival of the mice infected with the heteroresistant clones and the higher fungal burden in lungs and brain. Our results indicate that heteroresistance to itraconazole is intrinsic and increases the virulence of C. gattii. This phenomenon may represent an additional mechanism that contributes to relapses of cryptococcosis in patients during itraconazole therapy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii

Ferreira

Santos

Costa

et al. 2015

Antimicrob Agents Chemother

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Comparative Lipid Peroxidation and Apoptosis in Embryo‐Larval Zebrafish Exposed to 3 Azole Fungicides, Tebuconazole, Propiconazole, and Myclobutanil, at Environmentally Relevant Concentrations

Kumar

Awoyemi

Willis

et al. 2019

Enviro Toxic and Chemistry

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Azole fungicides have entered the aquatic environment through agricultural and residential runoff. In the present study, we compared the off‐target toxicity of tebuconazole, propiconazole, and myclobutanil using embryo‐larval zebrafish as a model. The aim of the present study was to investigate the relative toxicity of tebuconazole, propiconazole, and myclobutanil using multiple‐level endpoints such as behavioral endpoints and enzymatic and molecular biomarkers associated with their mode of action. Zebrafish embryos were exposed to azoles at environmentally relevant and high concentrations, 0.3, 1.0, and 1000 µg/L, starting at 5 h postfertilization (hpf) up to 48 hpf, as well as 5 d postfertilization (dpf). Relative mRNA expressions of cytochrome P450 family 51 lanosterol‐14α‐demethylase, glutathione S‐transferase, caspase 9, phosphoprotein p53, and BCL2‐associated X protein were measured to assess toxicity attributable to fungicides at the mRNA level, whereas caspase 3/7 (apoptosis) and 3,4‐methylenedioxyamphetamine (lipid peroxidation) levels were measured at the enzymatic level. Furthermore, mitochondrial dysfunction was measure through the Mito Stress test using the Seahorse XFe24 at 48 hpf. In addition, light to dark movement behavior was monitored at 5 dpf using Danio Vision® to understand adverse effects at the organismal level. There was no significant difference in the light to dark behavior with exposure to azoles compared to controls. The molecular biomarkers indicated that propiconazole and myclobutanil induced lipid peroxidation, oxidative stress, and potentially apoptosis at environmentally relevant concentrations (0.3 and 1 µg/L). The results from the mitochondrial respiration assay indicated a slight decrease in spare respiratory capacity with an acute exposure (48 hpf) to all 3 azoles at 1000 µg/L. Based on the present results, propiconazole and myclobutanil are acutely toxic compared to tebuconazole in aquatic organisms at environmentally relevant concentrations. Environ Toxicol Chem 2019;38:1455–1466. © 2019 SETAC

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Interaction of Nanoparticles with Microbes

Shende

Rajput

Gorovtsov

et al. 2021

Advances in Science, Technology &Amp; Innovation

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The role of oxidative and nitrosative bursts caused by azoles and amphotericin B against the fungal pathogen Cryptococcus gattii

Abstract: Oxidative and nitrosative bursts play an important role in the antifungal activity of itraconazole and amphotericin B against C. gattii.

Cited by 98 publications

References 32 publications

Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii

Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii

Comparative Lipid Peroxidation and Apoptosis in Embryo‐Larval Zebrafish Exposed to 3 Azole Fungicides, Tebuconazole, Propiconazole, and Myclobutanil, at Environmentally Relevant Concentrations

Interaction of Nanoparticles with Microbes

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