Erratum for Mor et al., “Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids”

Mor, Visesato; Rella, Antonella; Farnoud, Amir M.; Singh, Ashutosh; Munshi, Mansa; Bryan, Arielle M.; Naseem, Saadia; Konopka, James B.; Ojima, Iwao; Büllesbach, Erika E.; Ashbaugh, Alan; Linke, Michael J.; Cushion, Melanie T.; Collins, Margaret S.; Ananthula, Hari Krishna; Sallans, Larry; Desai, Pankaj B.; Wiederhold, Nathan P.; Fothergill, Annette W.; Kirkpatrick, William R.; Patterson, Thomas; Wong, Lai Hong; Sinha, Sunita; Giaever, Guri; Nislow, Corey; Flaherty, Patrick; Pan, Xuewen; Cesar, Gabriele Vargas; Tavares, Patricia de Melo; Frasés, Susana; Miranda, Kildare; Rodrigues, Márcio L.; Luberto, Chiara; Nimrichter, Leonardo; Poeta, Maurizio Del

doi:10.1128/mbio.00188-18

Cited by 7 publications

(6 citation statements)

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“…More recently, desired lowering of fungal GlcCer can be reached by reducing the biosynthesis of the lipid. Well tolerated acylhydrazones have been identified as specific inhibitors of fungal GCS, an enzyme that fundamentally differs from the mammalian counterpart and that is not inhibited by acylhydrazones (Lazzarini et al, 2018; Mor et al, 2018). Pharmaceutical reduction of fungal GlcCer is now envisioned as new opportunity to combat fungal infections, including cryptococcosis.…”

Section: Introduction To Glycosphingolipidsmentioning

confidence: 99%

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

Aerts

Artola

Eijk

et al. 2019

Front. Cell Dev. Biol.

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Glycosphingolipids (GSLs), the main topic of this review, are a subclass of sphingolipids. With their glycans exposed to the extracellular space, glycosphingolipids are ubiquitous components of the plasma membrane of cells. GSLs are implicated in a variety of biological processes including specific infections. Several pathogens use GSLs at the surface of host cells as binding receptors. In addition, lipid-rafts in the plasma membrane of host cells may act as platform for signaling the presence of pathogens. Relatively common in man are inherited deficiencies in lysosomal glycosidases involved in the turnover of GSLs. The associated storage disorders (glycosphingolipidoses) show lysosomal accumulation of substrate(s) of the deficient enzyme. In recent years compounds have been identified that allow modulation of GSLs levels in cells. Some of these agents are well tolerated and already used to treat lysosomal glycosphingolipidoses. This review summarizes present knowledge on the role of GSLs in infection and subsequent immune response. It concludes with the thought to apply glycosphingolipid-lowering agents to prevent and/or combat infections.

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Section: Introduction To Glycosphingolipidsmentioning

confidence: 99%

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

Aerts

Artola

Eijk

et al. 2019

Front. Cell Dev. Biol.

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“…In this context, the fungal sphingolipid glucosylceramide (GlcCer) synthesis has emerged as a highly promising new target for the development of next-generation antifungal agents. − GlcCer is essential for the cell division of pathogenic fungi such as C. neoformans, Candida albicans ( C. albicans ), and Aspergillus fumigatus ( A. funigatus ) and responsible for their virulence. − It has been shown that fungal cells lacking GlcCer cannot replicate in neutral or alkaline environments. ,, This finding clearly indicates the importance of GlcCer for virulence in alveolar spaces, cerebrospinal fluid, or bloodstream of the host wherein the pH is neutral or alkaline and thus makes GlcCer a promising target for drug discovery. , As shown in Figure A, aromatic acylhydrazone 1 , bearing a salicylaldehyde-hydrazone moiety, selectively inhibited the synthesis of fungal GlcCer in a dose-dependent manner without affecting the synthesis of mammalian GlcCer. , When the efficacy of 1 and 2 was evaluated in vivo, using mice infected with C. neoformans , both compounds substantially improved the survival of mice, compared to the untreated ones (Figure B) . Moreover, 2 exhibited better antifungal activity than fluconazole which is a clinically used drug to treat fungal infections.…”

Section: Introductionmentioning

confidence: 99%

SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents

et al. 2019

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Recently, the fungal sphingolipid glucosylceramide (GlcCer) synthesis has emerged as a highly promising new target for drug discovery of next-generation antifungal agents, and we found two aromatic acylhydrazones as effective inhibitors of GlcCer synthesis based on HTP screening. In the present work, we have designed libraries of new aromatic acylhydrazones, evaluated their antifungal activities (MIC80 and time-kill profile) against C. neoformans, and performed an extensive SAR study, which led to the identification of five promising lead compounds, exhibiting excellent fungicidal activities with very large selectivity index. Moreover, two compounds demonstrated broad spectrum antifungal activity against six other clinically relevant fungal strains. These five lead compounds were examined for their synergism/cooperativity with five clinical drugs against seven fungal strains, and very encouraging results were obtained; e.g., the combination of all five lead compounds with voriconazole exhibited either synergistic or additive effect to all seven fungal strains.

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“…This approach has been successfully used in the last few years to identify drugs that present antifungal activity. For example, screening of synthetic drug libraries revealed two hydrazides, N=-(3-bromo-6-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative 3-bromo-N=-(3-bromo-4-hydroxybenzylidene benzohydrazide), that target the synthesis of fungal sphingolipids and that could be promising drugs for the treatment of cryptococcosis (19,20). A variation of these screenings is to test the activity of off-patent compounds, which is known as drug repurposing.…”

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confidence: 99%

Identification of Off-Patent Drugs That Show Synergism with Amphotericin B or That Present Antifungal Action against Cryptococcus neoformans and Candida spp

Rossi

Oliveira

Agreda-Mellon

et al. 2020

Antimicrob Agents Chemother

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Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some lipidic and liposomal formulations that present reduced toxicity are available, their price limits their application in developing countries. Flucytosine (5FC) has shown synergistic effect with AmB for treatment of some fungal infections, such as cryptococcosis, but again, its price is a limitation for its use in many regions. In the present work, we aimed to identify new drugs that have a minor effect on Cryptococcus neoformans, reducing its growth in the presence of subinhibitory concentrations of AmB. In the initial screening, we found fourteen drugs that had this pattern. Later, checkerboard assays of selected compounds, such as erythromycin, riluzole, nortriptyline, chenodiol, nisoldipine, promazine, chlorcyclizine, cloperastine, and glimepiride, were performed and all of them confirmed for their synergistic effect (fractional inhibitory concentration index [FICI] < 0.5). Additionally, toxicity of these drugs in combination with AmB was tested in mammalian cells and in zebrafish embryos. Harmless compounds, such as the antibiotic erythromycin, were found to have synergic activity with AmB, not only against C. neoformans but also against some Candida spp., in particular against Candida albicans. In parallel, we identified drugs that had antifungal activity against C. neoformans and found 43 drugs that completely inhibited the growth of this fungus, such as ciclopirox and auranofin. Our results expand our knowledge about antifungal compounds and open new perspectives in the treatment of invasive mycosis based on repurposing off-patent drugs.

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Erratum for Mor et al., “Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids”

Cited by 7 publications

References 0 publications

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents

Identification of Off-Patent Drugs That Show Synergism with Amphotericin B or That Present Antifungal Action against Cryptococcus neoformans and Candida spp

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