ROS formation is a differential contributory factor to the fungicidal action of Amphotericin B and Micafungin in Candida albicans

Guirao-Abad, José P.; Sánchez-Fresneda, Ruth; Alburquerque, Begoña; Hernández, José Antonio; Argüelles, Juan-Carlos

doi:10.1016/j.ijmm.2017.03.005

Cited by 45 publications

(48 citation statements)

References 29 publications

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“…We and other groups have previously reported that MF treatment induces structural remodelling of the cell wall in C. albicans, as evident in electron micrographs (14,15). Here, we show that the ␤-glucans located in the inner layer of the cell wall were exposed on the cell surface as consequence of the antifungal treatment ( Fig.…”

Section: Discussionsupporting

confidence: 74%

“…Subinhibitory doses of this echinocandin are able to unmask cell wall ␤-glucan, which participates in the production of proinflammatory cytokines released by murine macrophages (12,13). Micafungin (MF) has been shown to have a fungicidal action like caspofungin, and it exerts a postantifungal effect that kills diverse Candida spp., disturbs cell walls of viable organisms (14,15), reduces adherence to epithelial cells, and enhances the susceptibility to phagocytosis mediated by a murine macrophage cell line (14). Despite the fact that MF and caspofungin belong to the echinocandin family, differences in their pharmacokinetics, pharmacodynamics, adverse effects, and/or drug interactions have been reported (9).…”

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confidence: 99%

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Micafungin Enhances the Human Macrophage Response to Candida albicans through β-Glucan Exposure

Guirao-Abad

Sánchez-Fresneda

Machado

et al. 2018

Antimicrob Agents Chemother

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Micafungin belongs to the antifungal family of echinocandins, which act as noncompetitive inhibitors of the fungal cell wall β-1,3-d-glucan synthase. Since is the most prevalent pathogenic fungus in humans, we study the involvement of micafungin in the modulation of the inflammatory response developed by human tissue macrophages against The MIC for micafungin was 0.016 μg/ml on the SC5314 standard strain. Micafungin induced a drastic reduction in the number of exponential SC5314 viable cells, with the fungicidal effect being dependent on the cellular metabolic activity. Notably, micafungin also caused a structural remodelling of the cell wall, leading to exposure of the β-glucan and chitin content on the external surface. At the higher doses used (0.05 μg/ml), the antifungal also induced the blowing up of budding yeasts. In addition, preincubation with micafungin before exposure to human tissue macrophages enhanced the secretion of tumor necrosis factor alpha (TNF-α), interleukin-17A (IL-17A), and IL-10 cytokines. Our results strongly suggest that in treatment with micafungin, in addition to having the expected toxic antifungal effect, it potentiates the immune response, improving the interaction and activation of human macrophages, probably through the unmasking of β-glucans on the cell wall surface.

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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 99%

Micafungin Enhances the Human Macrophage Response to Candida albicans through β-Glucan Exposure

Guirao-Abad

Sánchez-Fresneda

Machado

et al. 2018

Antimicrob Agents Chemother

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“…Despite several decades of clinical use, AmB mechanism of action at the molecular level remains elusive and several models have been proposed based on extensive experimental research and theoretical studies [45][46][47][48]54,55,[58][59][60][61][62][63][64][65][66]. AmB has been shown to bind sterol-containing membranes of eukaryotic cells and to insert into the lipid bilayer forming pore-like supramolecular structures that can act as transmembrane ion channels, leading to increased membrane permeability, K + leakage, and disruption of ion transport [44,45,48,53].…”

Section: Amphotericin B Properties and Mode Of Actionmentioning

confidence: 99%

“…The fungicidal activity of AmB has also been attributed to vacuole disintegration resulting from trafficking of the drug to the vacuolar lumen via autophagy [70]. Moreover, oxidative cell damage to the lipid membrane that results from increased mitochondrial production and intracellular accumulation of reactive oxygen species (ROS) induced by AmB leads to impaired cellular functions and also contributes to the fungicidal activity of the drug [59,[63][64][65][66]. Better microbial adaptation to oxidative stress has been suggested to contribute to the development of AmB tolerance in some Aspergillus terreus strains [71].…”

Section: Amphotericin B Properties and Mode Of Actionmentioning

confidence: 99%

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

2020

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Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.

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“…Indeed, it has been postulated that antifungal agents like amphotericin B and azoles trigger a common oxidative-damage cellular death pathways in fungi such as Candida albicans, Saccharomyces cerevisiae, or Cryptococcus gattii (11)(12)(13)(14)(15). One of these studies showed that inhibition of mitochondrial activity by rotenone abolished amphotericin B-induced oxidative stress in yeast (14).…”

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confidence: 99%

Induction of Mitochondrial Reactive Oxygen Species Production by Itraconazole, Terbinafine, and Amphotericin B as a Mode of Action against Aspergillus fumigatus

Shekhova

Kniemeyer

Brakhage

2017

Antimicrob Agents Chemother

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Drug resistance in fungal pathogens is of incredible importance to global health, yet the mechanisms of drug action remain only loosely defined. Antifungal compounds have been shown to trigger the intracellular accumulation of reactive oxygen species (ROS) in human-pathogenic yeasts, but the source of those ROS remained unknown. In the present study, we examined the role of endogenous ROS for the antifungal activity of the three different antifungal substances itraconazole, terbinafine, and amphotericin B, which all target the fungal cell membrane. All three antifungals had an impact on fungal redox homeostasis by causing increased intracellular ROS production. Interestingly, the elevated ROS levels induced by antifungals were abolished by inhibition of the mitochondrial respiratory complex I with rotenone. Further, evaluation of lipid peroxidation using the thiobarbituric acid assay revealed that rotenone pretreatment decreased ROS-induced lipid peroxidation during incubation of with itraconazole and terbinafine. By applying the mitochondrion-specific lipid peroxidation probe MitoPerOx, we also confirmed that ROS are induced in mitochondria and subsequently cause significant oxidation of mitochondrial membrane in the presence of terbinafine and amphotericin B. To summarize, our study suggests that the induction of ROS production contributes to the ability of antifungal compounds to inhibit fungal growth. Moreover, mitochondrial complex I is the main source of deleterious ROS production in challenged with antifungal compounds.

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ROS formation is a differential contributory factor to the fungicidal action of Amphotericin B and Micafungin in Candida albicans

Cited by 45 publications

References 29 publications

Micafungin Enhances the Human Macrophage Response to Candida albicans through β-Glucan Exposure

Micafungin Enhances the Human Macrophage Response to Candida albicans through β-Glucan Exposure

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

Induction of Mitochondrial Reactive Oxygen Species Production by Itraconazole, Terbinafine, and Amphotericin B as a Mode of Action against Aspergillus fumigatus

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