S. cerevisiae Outer and Inner Membranes are Compromised upon Benzyl Alcohol Treatment

Although there are innovations in the treatment of diseases caused by fungi and medicines with multiple targets have been developed, the search for a drug with a broad spectrum and without any side effects continues to date. It is generally accepted that determining the cellular target responsible for the toxic effect opens up new possibilities for the development of new drugs. Especially the effects of antifungal agents on the surface components of the fungal cell, on cell wall synthesis and the identification of the target site are crucial in antifungal drug development. Thus studies on the fungal cell membranes in connection with the antifungal agents, aim to develop new strategies for the therapy of fungal infections. Antifungal agents targeting fungal cell wall and cell membrane components have increased in importance in clinical studies. In this study, understanding the mechanism of action of benzyl alcohol, a known membrane fluidizer, and the determination of its cellular targets are aimed. We have shown that in the presence of sorbitol, the osmotic stabilizer, benzyl alcohol becomes less effective against yeast cell. Moreover, benzyl alcohol disrupts cell membrane, causing leakage of ions to the extracellular medium. Nuclear membrane is distorted upon treatment of yeast cells with benzyl alcohol. Thus, we conclude that both outer and inner yeast cell membranes are compromised by the action of benzyl alcohol.

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The Chitin Connection

mBio ◽

10.1128/mbio.00056-12 ◽

2012 ◽

Vol 3 (2) ◽

Cited By ~ 20

Author(s):

David L. Goldman ◽

Alfin G. Vicencio

Keyword(s):

Cell Wall ◽

Cell Membrane ◽

Fungal Infections ◽

Allergic Inflammation ◽

Chitinase Activity ◽

Chitin Deacetylase ◽

Fungal Cell ◽

Content Type ◽

Covalently Linked

ABSTRACTChitin, a polymer ofN-acetylglucosamine, is an essential component of the fungal cell wall. Chitosan, a deacetylated form of chitin, is also important in maintaining cell wall integrity and is essential forCryptococcus neoformansvirulence. In their article, Gilbert et al. [N. M. Gilbert, L. G. Baker, C. A. Specht, and J. K. Lodge, mBio 3(1):e00007-12, 2012] demonstrate that the enzyme responsible for chitosan synthesis, chitin deacetylase (CDA), is differentially attached to the cell membrane and wall. Bioactivity is localized to the cell membrane, where it is covalently linked via a glycosylphosphatidylinositol (GPI) anchor. Findings from this study significantly enhance our understanding of cryptococcal cell wall biology. Besides the role of chitin in supporting structural stability, chitin and host enzymes with chitinase activity have an important role in host defense and modifying the inflammatory response. Thus, chitin appears to provide a link between the fungus and host that involves both innate and adaptive immune responses. Recently, there has been increased attention to the role of chitinases in the pathogenesis of allergic inflammation, especially asthma. We review these findings and explore the possible connection between fungal infections, the induction of chitinases, and asthma.

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Antifungal activity of the clove essential oil from Syzygium aromaticum on Candida, Aspergillus and dermatophyte species

Journal of Medical Microbiology ◽

10.1099/jmm.0.010538-0 ◽

2009 ◽

Vol 58 (11) ◽

pp. 1454-1462 ◽

Cited By ~ 226

Author(s):

Eugénia Pinto ◽

Luís Vale-Silva ◽

Carlos Cavaleiro ◽

Lígia Salgueiro

Keyword(s):

Antifungal Activity ◽

Essential Oil ◽

Cell Membrane ◽

Fungal Infections ◽

Yeast Cells ◽

Syzygium Aromaticum ◽

Clove Oil ◽

Fungal Cell ◽

Minimum Fungicidal Concentration ◽

Clove Essential Oil

The composition and antifungal activity of clove essential oil (EO), obtained from Syzygium aromaticum, were studied. Clove oil was obtained commercially and analysed by GC and GC-MS. The EO analysed showed a high content of eugenol (85.3 %). MICs, determined according to Clinical and Laboratory Standards Institute protocols, and minimum fungicidal concentration were used to evaluate the antifungal activity of the clove oil and its main component, eugenol, against Candida, Aspergillus and dermatophyte clinical and American Type Culture Collection strains. The EO and eugenol showed inhibitory activity against all the tested strains. To clarify its mechanism of action on yeasts and filamentous fungi, flow cytometric and inhibition of ergosterol synthesis studies were performed. Propidium iodide rapidly penetrated the majority of the yeast cells when the cells were treated with concentrations just over the MICs, meaning that the fungicidal effect resulted from an extensive lesion of the cell membrane. Clove oil and eugenol also caused a considerable reduction in the quantity of ergosterol, a specific fungal cell membrane component. Germ tube formation by Candida albicans was completely or almost completely inhibited by oil and eugenol concentrations below the MIC values. The present study indicates that clove oil and eugenol have considerable antifungal activity against clinically relevant fungi, including fluconazole-resistant strains, deserving further investigation for clinical application in the treatment of fungal infections.

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Recent Status and Advancements in the Development of Antifungal Agents: Highlights on Plant and Marine Based Antifungals

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190412102037 ◽

2019 ◽

Vol 19 (10) ◽

pp. 812-830 ◽

Cited By ~ 2

Author(s):

P. Marie Arockianathan ◽

Monika Mishra ◽

Rituraj Niranjan

Keyword(s):

Cell Wall ◽

Antifungal Agents ◽

Fungal Diseases ◽

Fungal Cell Wall ◽

Fungal Resistance ◽

Ergosterol Biosynthesis ◽

Fungal Cell ◽

Ergosterol Synthesis ◽

Glucan Synthesis ◽

Anti Fungal

The developing resistance in fungi has become a key challenge, which is being faced nowadays with the available antifungal agents in the market. Further search for novel compounds from different sources has been explored to meet this problem. The current review describes and highlights recent advancement in the antifungal drug aspects from plant and marine based sources. The current available antifungal agents act on specific targets on the fungal cell wall, like ergosterol synthesis, chitin biosynthesis, sphingolipid synthesis, glucan synthesis etc. We discuss some of the important anti-fungal agents like azole, polyene and allylamine classes that inhibit the ergosterol biosynthesis. Echinocandins inhibit β-1, 3 glucan synthesis in the fungal cell wall. The antifungals poloxins and nikkomycins inhibit fungal cell wall component chitin. Apart from these classes of drugs, several combinatorial therapies have been carried out to treat diseases due to fungal resistance. Recently, many antifungal agents derived from plant and marine sources showed potent activity. The renewed interest in plant and marine derived compounds for the fungal diseases created a new way to treat these resistant strains which are evident from the numerous literature publications in the recent years. Moreover, the compounds derived from both plant and marine sources showed promising results against fungal diseases. Altogether, this review article discusses the current antifungal agents and highlights the plant and marine based compounds as a potential promising antifungal agents.

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Gingerol Derivatives as 14α-demethylase Inhibitors: Design and Development of Natural, Safe Antifungals for Immune-compromised Patients

Letters in Drug Design & Discovery ◽

10.2174/1570180816666191025105752 ◽

2020 ◽

Vol 17 (7) ◽

pp. 918-928

Author(s):

Sweta Sharma ◽

Arpita Yadav

Keyword(s):

Cell Membranes ◽

Fungal Infections ◽

Dynamics Simulation ◽

Stable Complex ◽

Active Site Residues ◽

Design And Development ◽

Triazole Derivative ◽

Fungal Cell ◽

Term Administration ◽

Compromised Patients

Background: : Currently, clinically used drugs for internal fungal infections have severe side effects. Patients suffering from severe fungal infections and those at a constant risk of developing such infections require long-term administration of safe antifungals. Objective: : This work deals with the design and development of safe, non-toxic antifungals derived from natural compounds for immune-compromised patients, such as HIV patients, who are at a constant risk of developing internal fungal infections. Methods: : Molecular modeling, docking and molecular dynamics simulation studies were performed on the main constituents of ginger and their derivatives to study their capability to inhibit 14α- demethylase enzyme. Results: : Ergosterol is the key component of the fungal cell membrane for its integrity and rigidity, synthesized from lanosterol catalyzed by 14α-demethylase enzyme. In our studies, it is determined that 6-gingerol, 6-paradol, 6-shogaol and their imidazole and triazole derivatives can inhibit the synthesis of ergosterol thus weakening the fungal cell membranes. The triazole derivative of 6-gingerol forms enhanced binding interactions with the active site residues of 14α-demethylase, carries an affinity for catalytically required cofactor heme and forms a stable complex with time without the probability of premature expulsion. Thus, this compound inhibits the formation of ergosterol leading to weakened fungal cell membranes and eventually death of fungal cells. Conclusion: : The triazole derivative of 6-gingerol is recommended as a lead compound for the development of non-toxic antifungals.

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The newly synthesized thiazole derivatives as potential antifungal compounds against Candida albicans

Applied Microbiology and Biotechnology ◽

10.1007/s00253-021-11477-7 ◽

2021 ◽

Author(s):

Anna Biernasiuk ◽

Anna Berecka-Rycerz ◽

Anna Gumieniczek ◽

Maria Malm ◽

Krzysztof Z. Łączkowski ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Antifungal Activity ◽

Cell Membrane ◽

Mode Of Action ◽

Thiazole Derivatives ◽

Fungal Cell ◽

Erythrocyte Lysis ◽

Low Cytotoxicity ◽

High Antifungal Activity

Abstract Recently, the occurrence of candidiasis has increased dramatically, especially in immunocompromised patients. Additionally, their treatment is often ineffective due to the resistance of yeasts to antimycotics. Therefore, there is a need to search for new antifungals. A series of nine newly synthesized thiazole derivatives containing the cyclopropane system, showing promising activity against Candida spp., has been further investigated. We decided to verify their antifungal activity towards clinical Candida albicans isolated from the oral cavity of patients with hematological malignancies and investigate the mode of action on fungal cell, the effect of combination with the selected antimycotics, toxicity to erythrocytes, and lipophilicity. These studies were performed by the broth microdilution method, test with sorbitol and ergosterol, checkerboard technique, erythrocyte lysis assay, and reversed phase thin-layer chromatography, respectively. All derivatives showed very strong activity (similar and even higher than nystatin) against all C. albicans isolates with minimal inhibitory concentration (MIC) = 0.008–7.81 µg/mL Their mechanism of action may be related to action within the fungal cell wall structure and/or within the cell membrane. The interactions between the derivatives and the selected antimycotics (nystatin, chlorhexidine, and thymol) showed additive effect only in the case of combination some of them and thymol. The erythrocyte lysis assay confirmed the low cytotoxicity of these compounds as compared to nystatin. The high lipophilicity of the derivatives was related with their high antifungal activity. The present studies confirm that the studied thiazole derivatives containing the cyclopropane system appear to be a very promising group of compounds in treatment of infections caused by C. albicans. However, this requires further studies in vivo. Key points • The newly thiazoles showed high antifungal activity and some of them — additive effect in combination with thymol. • Their mode of action may be related with the influence on the structure of the fungal cell wall and/or the cell membrane. • The low cytotoxicity against erythrocytes and high lipophilicity of these derivatives are their additional good properties. Graphical abstract

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Vanillin and its derivatives, potential promising antifungal agents, inhibit Aspergillus flavus spores via destroying the integrity of cell membrane rather than cell wall

Grain & Oil Science and Technology ◽

10.1016/j.gaost.2021.03.002 ◽

2021 ◽

Author(s):

Qian Li ◽

Xiaoman Zhu

Keyword(s):

Cell Wall ◽

Cell Membrane ◽

Aspergillus Flavus ◽

Antifungal Agents

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The Fungal Cell Wall — A Target For Lipopeptide Antifungal Agents

New Approaches for Antifungal Drugs ◽

10.1007/978-1-4899-6729-9_4 ◽

1992 ◽

pp. 46-63 ◽

Cited By ~ 2

Author(s):

Robert S. Gordee ◽

Manuel Debono ◽

Thomas R. Parr

Keyword(s):

Cell Wall ◽

Antifungal Agents ◽

Fungal Cell Wall ◽

Fungal Cell

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Spatial Distribution of a Porphyrin-Based Photosensitizer Reveals Mechanism of Photodynamic Inactivation of Candida albicans

Frontiers in Medicine ◽

10.3389/fmed.2021.641244 ◽

2021 ◽

Vol 8 ◽

Author(s):

Thomas Voit ◽

Fabian Cieplik ◽

Johannes Regensburger ◽

Karl-Anton Hiller ◽

Anita Gollmer ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Fungal Infections ◽

Cell Envelope ◽

Antimicrobial Photodynamic Therapy ◽

Fungal Cell ◽

Before And After ◽

Antifungal Action ◽

Complete Cell ◽

Further Development

The antimicrobial photodynamic therapy (aPDT) is a promising approach for the control of microbial and especially fungal infections such as mucosal mycosis. TMPyP [5,10,15, 20-tetrakis(1-methylpyridinium-4-yl)-porphyrin tetra p-toluenesulfonate] is an effective photosensitizer (PS) that is commonly used in aPDT. The aim of this study was to examine the localization of TMPyP in Candida albicans before and after irradiation with visible light to get information about the cellular mechanism of antifungal action of the photodynamic process using this PS. Immediately after incubation of C. albicans with TMPyP, fluorescence microscopy revealed an accumulation of the PS in the cell envelope. After irradiation with blue light the complete cell showed red fluorescence, which indicates, that aPDT is leading to a damage in the cell wall with following influx of PS into the cytosol. Incubation of C. albicans with Wheat Germ Agglutinin (WGA) could confirm the cell wall as primary binding site of TMPyP. The finding that the porphyrin accumulates in the fungal cell wall and does not enter the interior of the cell before irradiation makes it unlikely that resistances can emerge upon aPDT. The results of this study may help in further development and modification of PS in order to increase efficacy against fungal infections such as those caused by C. albicans.

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