scholarly journals The Viscoelastic Properties of the Fungal Cell Wall Allow Traffic of AmBisome as Intact Liposome Vesicles

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Louise Walker ◽  
Prashant Sood ◽  
Megan D. Lenardon ◽  
Gillian Milne ◽  
Jon Olson ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Cell Membrane ◽  
Amphotericin B ◽  
Mode Of Action ◽  
Viscoelastic Properties ◽  
Fungal Cell Wall ◽  
Fungal Cell ◽  
Pass Through ◽  
Cell Wall Porosity

ABSTRACT The fungal cell wall is a critically important structure that represents a permeability barrier and protective shield. We probed Candida albicans and Cryptococcus neoformans with liposomes containing amphotericin B (AmBisome), with or without 15-nm colloidal gold particles. The liposomes have a diameter of 60 to 80 nm, and yet their mode of action requires them to penetrate the fungal cell wall to deliver amphotericin B to the cell membrane, where it binds to ergosterol. Surprisingly, using cryofixation techniques with electron microscopy, we observed that the liposomes remained intact during transit through the cell wall of both yeast species, even though the predicted porosity of the cell wall (pore size, ~5.8 nm) is theoretically too small to allow these liposomes to pass through intact. C. albicans mutants with altered cell wall thickness and composition were similar in both their in vitro AmBisome susceptibility and the ability of liposomes to penetrate the cell wall. AmBisome exposed to ergosterol-deficient C. albicans failed to penetrate beyond the mannoprotein-rich outer cell wall layer. Melanization of C. neoformans and the absence of amphotericin B in the liposomes were also associated with a significant reduction in liposome penetration. Therefore, AmBisome can reach cell membranes intact, implying that fungal cell wall viscoelastic properties are permissive to vesicular structures. The fact that AmBisome can transit through chemically diverse cell wall matrices when these liposomes are larger than the theoretical cell wall porosity suggests that the wall is capable of rapid remodeling, which may also be the mechanism for release of extracellular vesicles. IMPORTANCE AmBisome is a broad-spectrum fungicidal antifungal agent in which the hydrophobic polyene antibiotic amphotericin B is packaged within a 60- to 80-nm liposome. The mode of action involves perturbation of the fungal cell membrane by selectively binding to ergosterol, thereby disrupting membrane function. We report that the AmBisome liposome transits through the cell walls of both Candida albicans and Cryptococcus neoformans intact, despite the fact that the liposome is larger than the theoretical cell wall porosity. This implies that the cell wall has deformable, viscoelastic properties that are permissive to transwall vesicular traffic. These observations help explain the low toxicity of AmBisome, which can deliver its payload directly to the cell membrane without unloading the polyene in the cell wall. In addition, these findings suggest that extracellular vesicles may also be able to pass through the cell wall to deliver soluble and membrane-bound effectors and other molecules to the extracellular space.

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 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 A Whole-Cell Candida albicans Assay for the Detection of Inhibitors towards Fungal Cell Wall Synthesis and Assembly.

1995 ◽  
Vol 48 (4) ◽  
pp. 306-310 ◽  
Author(s):  
DAVID J. FROST ◽  
KIM D. BRANDT ◽  
DAVID CUGIER ◽  
ROBERT GOLDMAN
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Fungal Cell Wall ◽  
Cell Wall Synthesis ◽  
Fungal Cell ◽  
Whole Cell

scholarly journals Analysis of the 3H8 antigen of Candida albicans reveals new aspects of the organization of fungal cell wall proteins

2018 ◽  
Vol 18 (4) ◽  
Author(s):  
Rafael Sentandreu ◽  
Antonio Caminero ◽  
Itzel Rentería ◽  
Claudia León-Ramirez ◽  
Luis González-de-la-Vara ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Fungal Cell Wall ◽  
Cell Wall Proteins ◽  
Fungal Cell

scholarly journals Iron alters the cell wall composition and intracellular lactate to affect Candida albicans susceptibility to antifungals and host immune response

2020 ◽  
Vol 295 (29) ◽  
pp. 10032-10044 ◽  
Author(s):  
Aparna Tripathi ◽  
Elisabetta Liverani ◽  
Alexander Y. Tsygankov ◽  
Sumant Puri
Keyword(s):  
Immune Response ◽  
Cell Wall ◽  
Candida Albicans ◽  
Signaling Pathways ◽  
Host Immune Response ◽  
Fungal Cell Wall ◽  
Mitogen Activated Protein Kinase ◽  
Fungal Cell ◽  
High Iron ◽  
Cell Wall Architecture

Fungal pathogen Candida albicans has a complex cell wall consisting of an outer layer of mannans and an inner layer of β-glucans and chitin. The fungal cell wall is the primary target for antifungals and is recognized by host immune cells. Environmental conditions such as carbon sources, pH, temperature, and oxygen tension can modulate the fungal cell wall architecture. Cellular signaling pathways, including the mitogen-activated protein kinase (MAPK) pathways, are responsible for sensing environmental cues and mediating cell wall alterations. Although iron has recently been shown to affect β-1,3-glucan exposure on the cell wall, we report here that iron changes the composition of all major C. albicans cell wall components. Specifically, high iron decreased the levels of mannans (including phosphomannans) and chitin; and increased β-1,3-glucan levels. These changes increased the resistance of C. albicans to cell wall-perturbing antifungals. Moreover, high iron cells exhibited adequate mitochondrial functioning; leading to a reduction in accumulation of lactate that signals through the transcription factor Crz1 to induce β-1,3-glucan masking in C. albicans. We show here that iron-induced changes in β-1,3-glucan exposure are lactate-dependent; and high iron causes β-1,3-glucan exposure by preventing lactate-induced, Crz1-mediated inhibition of activation of the fungal MAPK Cek1. Furthermore, despite exhibiting enhanced antifungal resistance, high iron C. albicans cells had reduced survival upon phagocytosis by macrophages. Our results underscore the role of iron as an environmental signal in multiple signaling pathways that alter cell wall architecture in C. albicans, thereby affecting its survival upon exposure to antifungals and host immune response.

scholarly journals (R)-(+)-β-Citronellol and (S)-(−)-β-Citronellol in Combination with Amphotericin B against Candida Spp.

2020 ◽  
Vol 21 (5) ◽  
pp. 1785 ◽  
Author(s):  
Daniele Silva ◽  
Hermes Diniz-Neto ◽  
Laísa Cordeiro ◽  
Maria Silva-Neta ◽  
Shellygton Silva ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Minimum Inhibitory Concentration ◽  
Amphotericin B ◽  
Mechanism Of Action ◽  
Inhibitory Concentration ◽  
Association Studies ◽  
Antifungal Drugs ◽  
Candida Spp ◽  
Fungal Cell

The enantiomers (R)-(+)-β-citronellol and (S)-(−)-β-citronellol are present in many medicinal plants, but little is understood about their bioactivity against Candida yeasts. This study aimed to evaluate the behavior of positive and negative enantiomers of β-citronellol on strains of Candida albicans and C. tropicalis involved in candidemia. The minimum inhibitory concentration (MIC) and minimum fungicide concentration (MFC) were determined. The evaluation of growth kinetics, mechanism of action, and association studies with Amphotericin B (AB) using the checkerboard method was also performed. R-(+)-β-citronellol and S-(−)-β-citronellol presented a MIC50% of 64 µg/mL and a MFC50% of 256 µg/mL for C. albicans strains. For C. tropicalis, the isomers exhibited a MIC50% of 256 µg/mL and a MFC50% of 1024 µg/mL. In the mechanism of action assay, both substances displayed an effect on the fungal membrane but not on the fungal cell wall. Synergism and indifference were observed in the association of R-(+)-β-citronellol and AB, while the association between S-(−)-β-citronellol and AB displayed synergism, additivity, and indifference. In conclusion, both isomers of β-citronellol presented a similar profile of antifungal activity. Hence, they can be contemplated in the development of new antifungal drugs providing that further research is conducted about their pharmacology and toxicity.

Undressing the Fungal Cell Wall/Cell Membrane - the Antifungal Drug Targets

2013 ◽  
Vol 19 (20) ◽  
pp. 3738-3747 ◽  
Author(s):  
Rui Tada ◽  
Jean-Paul Latge ◽  
Vishukumar Aimanianda
Keyword(s):  
Cell Wall ◽  
Cell Membrane ◽  
Drug Targets ◽  
Antifungal Drug ◽  
Fungal Cell Wall ◽  
Fungal Cell ◽  
Wall Cell
Sign in / Sign up

Export Citation Format

Share Document