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

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.

scholarly journals High-Throughput Screening Identifies Genes Required forCandida albicansInduction of Macrophage Pyroptosis

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Teresa R. O’Meara ◽  
Kwamaa Duah ◽  
Cynthia X. Guo ◽  
Michelle E. Maxson ◽  
Ryan G. Gaudet ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Immune Cells ◽  
High Throughput Screening ◽  
Immune Cell ◽  
Fungal Infections ◽  
Innate Immune ◽  
Fungal Cell ◽  
Content Type ◽  
Cell Wall Remodeling

ABSTRACTThe innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example,Candida albicansundergoes a morphogenetic switch coupled to cell wall remodeling upon phagocytosis by macrophages and then induces macrophage pyroptosis, an inflammatory cell death program. To elucidate the genetic circuitry through whichC. albicansorchestrates this host response, we performed the first large-scale analysis ofC. albicansinteractions with mammalian immune cells. We identified 98C. albicansgenes that enable macrophage pyroptosis without influencing fungal cell morphology in the macrophage, including specific determinants of cell wall biogenesis and the Hog1 signaling cascade. Using these mutated genes, we discovered that defects in the activation of pyroptosis affect immune cell recruitment during infection. Examining host circuitry required for pyroptosis in response toC. albicansinfection, we discovered that inflammasome priming and activation can be decoupled. Finally, we observed thatapoptosis-associatedspeck-like protein containing aCARD (ASC) oligomerization can occur prior to phagolysosomal rupture byC. albicanshyphae, demonstrating that phagolysosomal rupture is not the inflammasome activating signal. Taking the data together, this work defines genes that enable fungal cell wall remodeling and activation of macrophage pyroptosis independently of effects on morphogenesis and identifies macrophage signaling components that are required for pyroptosis in response toC. albicansinfection.IMPORTANCECandida albicansis a natural member of the human mucosal microbiota that can also cause superficial infections and life-threatening systemic infections, both of which are characterized by inflammation. Host defense relies mainly on the ingestion and destruction ofC. albicansby innate immune cells, such as macrophages and neutrophils. Although someC. albicanscells are killed by macrophages, most undergo a morphological change and escape by inducing macrophage pyroptosis. Here, we investigated theC. albicansgenes and host factors that promote macrophage pyroptosis in response to intracellular fungi. This work provides a foundation for understanding how host immune cells interact withC. albicansand may lead to effective strategies to modulate inflammation induced by fungal infections.

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

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

scholarly journals Screening and Antifungal Activity of a β-Carboline Derivative against Cryptococcus neoformans and C. gattii

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Kátia Santana Cruz ◽  
Emerson Silva Lima ◽  
Marcia de Jesus Amazonas da Silva ◽  
Erica Simplício de Souza ◽  
Andreia Montoia ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Active Compound ◽  
Cell Walls ◽  
Human Fibroblasts ◽  
Lead Compound ◽  
Fungal Cell ◽  
Fungal Cell Walls

Background. Cryptococcosis is a fungal disease of bad prognosis due to its pathogenicity and the toxicity of the drugs used for its treatment. The aim of this study was to investigate the medicinal potential of carbazole and β-carboline alkaloids and derivatives against Cryptococcus neoformans and C. gattii. Methods. MICs were established in accordance with the recommendations of the Clinical and Laboratory Standards Institute for alkaloids and derivatives against C. neoformans and C. gattii genotypes VNI and VGI, respectively. A single active compound was further evaluated against C. neoformans genotypes VNII, VNIII, and VNIV, C. gattii genotypes VGI, VGIII, and VGIV, Candida albicans ATCC 36232, for cytotoxicity against the MRC-5 lineage of human fibroblasts and for effects on fungal cells (cell wall, ergosterol, and leakage of nucleic acids). Results. Screening of 11 compounds revealed 8-nitroharmane as a significant inhibitor (MIC 40 μg/mL) of several C. neoformans and C. gattii genotypes. It was not toxic to fibroblasts (IC50 > 50 µg/mL) nor did it alter fungal cell walls or the concentration of ergosterol in C. albicans or C. neoformans. It increased leakage of substances that absorb at 260 nm. Conclusions. The synthetic β-carboline 8-nitroharmane significantly inhibits pathogenic Cryptococcus species and is interesting as a lead compound towards new therapy for Cryptococcus infections.

scholarly journals 11g, a Potent Antifungal Candidate, Enhances Candida albicans Immunogenicity by Unmasking β-Glucan in Fungal Cell Wall

2020 ◽  
Vol 11 ◽  
Author(s):  
Xin Huang ◽  
Yu Liu ◽  
Tingjunhong Ni ◽  
Liping Li ◽  
Lan Yan ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Fungal Cell Wall ◽  
Fungal Cell

scholarly journals Targeting adhesion in fungal pathogen Candida albicans

2020 ◽  
Author(s):  
Harlei Martin ◽  
Kevin Kavanagh ◽  
Trinidad Velasco-Torrijos
Keyword(s):  
Candida Albicans ◽  
Fungal Infections ◽  
Initial Step ◽  
Infection Process ◽  
Host Cells ◽  
Fungal Cell ◽  
Receptor Interactions ◽  
Genes Encoding ◽  
Invasive Infections ◽  
Wall Components

Fungal infections with increasing resistance to conventional therapies are a growing concern. Candida albicans is a major opportunistic yeast responsible for mucosal and invasive infections. Targeting the initial step of the infection process (i.e., C. albicans adhesion to the host cell) is a promising strategy. A wide variety of molecules can interfere with adhesion processes via an assortment of mechanisms. Herein, we focus on how small molecules disrupt biosynthesis of fungal cell wall components and membrane structure, prevent the localization of GPI-anchor proteins, inhibit production of enzymes involved in adhesion, downregulate genes encoding adhesins and competitively inhibit receptor interactions. As a result, adhesion of C. albicans to host cells is reduced, paving the way to new classes of antifungal agents.

scholarly journals The Chitin Connection

mBio ◽  
2012 ◽  
Vol 3 (2) ◽  
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.

scholarly journals Nanoscopic cell-wall architecture of an immunogenic ligand in Candida albicans during antifungal drug treatment

2016 ◽  
Vol 27 (6) ◽  
pp. 1002-1014 ◽  
Author(s):  
Jia Lin ◽  
Michael J. Wester ◽  
Matthew S. Graus ◽  
Keith A. Lidke ◽  
Aaron K. Neumann
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Cell Walls ◽  
Innate Immune ◽  
Immune Recognition ◽  
Cell Wall Polysaccharide ◽  
Stochastic Optical Reconstruction Microscopy ◽  
Before And After ◽  
Antifungal Chemotherapy ◽  
Optical Reconstruction

The cell wall of Candida albicans is composed largely of polysaccharides. Here we focus on β-glucan, an immunogenic cell-wall polysaccharide whose surface exposure is often restricted, or “masked,” from immune recognition by Dectin-1 on dendritic cells (DCs) and other innate immune cells. Previous research suggested that the physical presentation geometry of β-glucan might determine whether it can be recognized by Dectin-1. We used direct stochastic optical reconstruction microscopy to explore the fine structure of β-glucan exposed on C. albicans cell walls before and after treatment with the antimycotic drug caspofungin, which alters glucan exposure. Most surface-accessible glucan on C. albicans yeast and hyphae is limited to isolated Dectin-1–binding sites. Caspofungin-induced unmasking caused approximately fourfold to sevenfold increase in total glucan exposure, accompanied by increased phagocytosis efficiency of DCs for unmasked yeasts. Nanoscopic imaging of caspofungin-unmasked C. albicans cell walls revealed that the increase in glucan exposure is due to increased density of glucan exposures and increased multiglucan exposure sizes. These findings reveal that glucan exhibits significant nanostructure, which is a previously unknown physical component of the host– Candida interaction that might change during antifungal chemotherapy and affect innate immune activation.

scholarly journals Structure, Cellular Distribution, Antigenicity, and Biological Functions of Fonsecaea pedrosoi Ceramide Monohexosides

2005 ◽  
Vol 73 (12) ◽  
pp. 7860-7868 ◽  
Author(s):  
Leonardo Nimrichter ◽  
Mariana D. Cerqueira ◽  
Eduardo A. Leitão ◽  
Kildare Miranda ◽  
Ernesto S. Nakayasu ◽  
...  
Keyword(s):  
Cell Wall ◽  
Structural Difference ◽  
Structural Diversity ◽  
Fungal Species ◽  
Hydroxyl Group ◽  
Current Evidence ◽  
Fonsecaea Pedrosoi ◽  
Fungal Cell ◽  
Long Chain Base ◽  
Antifungal Action

ABSTRACT Monohexosylceramides (CMHs, or cerebrosides) have been reported as membrane and cell wall constituents of both pathogenic and nonpathogenic fungi, presenting remarkable differences in their ceramide moiety compared to mammalian CMHs. Current evidence suggests that CMHs are involved in fungal differentiation and growth and contribute to host immune response. Here we describe a structural diversity between cerebrosides obtained from different forms of the human pathogen Fonsecaea pedrosoi. The major CMH species produced by conidial forms displayed the same structure previously demonstrated by our group for mycelia, an N-2′-hydroxyhexadecanoyl-1-β-d-glucopyranosyl-9-methyl-4,8-sphingadienine. However, the major cerebroside species purified from sclerotic cells carries an additional hydroxyl group, bound to its long-chain base. The structural difference between cerebrosides from mycelial and sclerotic cells was apparently not relevant for their antigenicity, since they were both recognized at similar levels by sera from individuals with chromoblastomycosis and a monoclonal antibody to a conserved cerebroside structure. Preincubation of fungal cells with anti-CMH monoclonal antibodies had no effect on the interaction of F. pedrosoi sclerotic cells with murine macrophages. In contrast to what has been described for other fungal species, sclerotic bodies are resistant to the antifungal action of anti-CMH antibodies. Immunofluorescence analysis showed that recognition of sclerotic cells by these antibodies only occurs at cell wall regions in which melanization is not evident. Accordingly, melanin removal with alkali results in an increased reaction of fungal cells with anti-CMH antibodies. Our results indicate that cerebroside expression in F. pedrosoi cells is associated with dimorphism and melanin assembly on the fungal cell wall.

scholarly journals Fluconazole and Lipopeptide Surfactin Interplay During Candida albicans Plasma Membrane and Cell Wall Remodeling Increases Fungal Immune System Exposure

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 314 ◽  
Author(s):  
Jakub Suchodolski ◽  
Daria Derkacz ◽  
Jakub Muraszko ◽  
Jarosław J. Panek ◽  
Aneta Jezierska ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Plasma Membrane ◽  
Immune System ◽  
Antifungal Drugs ◽  
Stable Complex ◽  
Host Immune System ◽  
Chitin Synthesis ◽  
Fungal Cell ◽  
In Silico Studies

Recognizing the β-glucan component of the Candida albicans cell wall is a necessary step involved in host immune system recognition. Compounds that result in exposed β-glucan recognizable to the immune system could be valuable antifungal drugs. Antifungal development is especially important because fungi are becoming increasingly drug resistant. This study demonstrates that lipopeptide, surfactin, unmasks β-glucan when the C. albicans cells lack ergosterol. This observation also holds when ergosterol is depleted by fluconazole. Surfactin does not enhance the effects of local chitin accumulation in the presence of fluconazole. Expression of the CHS3 gene, encoding a gene product resulting in 80% of cellular chitin, is downregulated. C. albicans exposure to fluconazole changes the composition and structure of the fungal plasma membrane. At the same time, the fungal cell wall is altered and remodeled in a way that makes the fungi susceptible to surfactin. In silico studies show that surfactin can form a complex with β-glucan. Surfactin forms a less stable complex with chitin, which in combination with lowering chitin synthesis, could be a second anti-fungal mechanism of action of this lipopeptide.

scholarly journals The Antifungal Action Mode of N-Phenacyldibromobenzimidazoles

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5463
Author(s):  
Monika Staniszewska ◽  
Łukasz Kuryk ◽  
Aleksander Gryciuk ◽  
Joanna Kawalec ◽  
Marta Rogalska ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Wall ◽  
Cell Membrane ◽  
Chitinolytic Activity ◽  
Irreversible Damage ◽  
Fungal Cell ◽  
Action Mode ◽  
Structure Activity ◽  
Dependent Inhibition ◽  
Antifungal Action

Our study aimed to characterise the action mode of N-phenacyldibromobenzimidazoles against C. albicans and C. neoformans. Firstly, we selected the non-cytotoxic most active benzimidazoles based on the structure–activity relationships showing that the group of 5,6-dibromobenzimidazole derivatives are less active against C. albicans vs. 4,6-dibromobenzimidazole analogues (5e–f and 5h). The substitution of chlorine atoms to the benzene ring of the N-phenacyl substituent extended the anti-C. albicans action (5e with 2,4-Cl2 or 5f with 3,4-Cl2). The excellent results for N-phenacyldibromobenzimidazole 5h against the C. albicans reference and clinical isolate showed IC50 = 8 µg/mL and %I = 100 ± 3, respectively. Compound 5h was fungicidal against the C. neoformans isolate. Compound 5h at 160–4 µg/mL caused irreversible damage of the fungal cell membrane and accidental cell death (ACD). We reported on chitinolytic activity of 5h, in accordance with the patterns observed for the following substrates: 4-nitrophenyl-N-acetyl-β-d-glucosaminide and 4-nitrophenyl-β-d-N,N′,N″-triacetylchitothiose. Derivative 5h at 16 µg/mL: (1) it affected cell wall by inducing β-d-glucanase, (2) it caused morphological distortions and (3) osmotic instability in the C. albicans biofilm-treated. Compound 5h exerted Candida-dependent inhibition of virulence factors.

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