Effects of subinhibitory dose of amphotericin B on cell wall biosynthesis in Candida Albicans

Amphotericin B (Ampho B) is a fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically. We tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression in patients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with <11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage, liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.

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Putative Role of β-1,3 Glucans in Candida albicans Biofilm Resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01056-06 ◽

2006 ◽

Vol 51 (2) ◽

pp. 510-520 ◽

Cited By ~ 250

Author(s):

Jeniel Nett ◽

Leslie Lincoln ◽

Karen Marchillo ◽

Randall Massey ◽

Kathleen Holoyda ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Cell Viability ◽

Amphotericin B ◽

Cell Walls ◽

Positive Impact ◽

Indirect Evidence ◽

Phenotypic Properties

ABSTRACT Biofilms are microbial communities, embedded in a polymeric matrix, growing attached to a surface. Nearly all device-associated infections involve growth in the biofilm life style. Biofilm communities have characteristic architecture and distinct phenotypic properties. The most clinically important phenotype involves extraordinary resistance to antimicrobial therapy, making biofilm infections very difficulty to cure without device removal. The current studies examine drug resistance in Candida albicans biofilms. Similar to previous reports, we observed marked fluconazole and amphotericin B resistance in a C. albicans biofilm both in vitro and in vivo. We identified biofilm-associated cell wall architectural changes and increased β-1,3 glucan content in C. albicans cell walls from a biofilm compared to planktonic organisms. Elevated β-1,3 glucan levels were also found in the surrounding biofilm milieu and as part of the matrix both from in vitro and in vivo biofilm models. We thus investigated the possible contribution of β-glucans to antimicrobial resistance in Candida albicans biofilms. Initial studies examined the ability of cell wall and cell supernatant from biofilm and planktonic C. albicans to bind fluconazole. The cell walls from both environmental conditions bound fluconazole; however, four- to fivefold more compound was bound to the biofilm cell walls. Culture supernatant from the biofilm, but not planktonic cells, bound a measurable amount of this antifungal agent. We next investigated the effect of enzymatic modification of β-1,3 glucans on biofilm cell viability and the susceptibility of biofilm cells to fluconazole and amphotericin B. We observed a dose-dependent killing of in vitro biofilm cells in the presence of three different β-glucanase preparations. These same concentrations had no impact on planktonic cell viability. β-1,3 Glucanase markedly enhanced the activity of both fluconazole and amphotericin B. These observations were corroborated with an in vivo biofilm model. Exogenous biofilm matrix and commercial β-1,3 glucan reduced the activity of fluconazole against planktonic C. albicans in vitro. In sum, the current investigation identified glucan changes associated with C. albicans biofilm cells, demonstrated preferential binding of these biofilm cell components to antifungals, and showed a positive impact of the modification of biofilm β-1,3 glucans on drug susceptibility. These results provide indirect evidence suggesting a role for glucans in biofilm resistance and present a strong rationale for further molecular dissection of this resistance mechanism to identify new drug targets to treat biofilm infections.

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PL002 Regulatory networks controlling virulence, morphology and cell wall biosynthesis in Candida albicans

International Journal of Medical Microbiology Supplements ◽

10.1016/s1433-1128(03)80544-2 ◽

2003 ◽

Vol 293 ◽

pp. 89-90

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Regulatory Networks ◽

Cell Wall Biosynthesis

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

mBio ◽

10.1128/mbio.02383-17 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 55

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21051785 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1785 ◽

Cited By ~ 4

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.

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A review on antifungal agents against Candida albicans and Aspergillus niger

International Journal of Biological and Pharmaceutical Sciences Archive ◽

10.53771/ijbpsa.2021.2.1.0061 ◽

2021 ◽

Vol 2 (1) ◽

pp. 042-054

Author(s):

Vishnuvardhini R ◽

Priya R Iyer

Keyword(s):

Cell Wall ◽

Natural Products ◽

Candida Albicans ◽

Aspergillus Niger ◽

Amphotericin B ◽

Antifungal Agents ◽

Fungal Infections ◽

Natural Compounds ◽

Synthetic Compounds ◽

Synthetic Drugs

Candidiasis is the fungal infection caused by Candida albicans. It causes different type of candidiasis infections in the blood, heart, eyes, brain, bones also other parts of our body. Different types of candidiasis are vaginal candidiasis, pulmonary candidiasis, oral candidiasis. It may be acute or chronic. It can be cured by using natural compounds or synthetic compounds or semisynthetic compounds. Apergillosis is the fungal infections in human caused by Aspergillus niger. Aspergillosis infections are classified into allergic pulmonary sinusitis, cutaneous aspergillosis, invasive aspergillosis, chronic necrotising pulmonary aspergillosis can be cured by using synthetic compounds like intravenous injections, oral medicines of capsules, tropical medicines like creams and some other natural products from plants. Natural products like saponins, flavonoids, alkaloids, xanthones, lectins and polypeptides, quinones, terpenoids, coumarins, essential oils and other compounds are the secondary metabolites extracted from the plants. Those plants are effective against fungal infections. Synthetic drugs like Azole group of drugs composed of imidazoles which includes miconazole, clotrimazole, ketoconazole, and triazoles include itraconazole, Posaconazole, isavuconazole are used to inhibit the ergosterol synthesis of cell membrane of fungi. Echinocandins are antifungal agent and it is used to disrupt the cell wall of fungi and inhibiting the synthesis of beta- 1,3 glucan fungal cell wall. Echinocandins are classified into caspofungin, anidulafungin, micafungin which having antifungal activity and amphotericin B used to treat both candidiasis and aspergillosis. Combination of drugs like synthetic drugs and natural compounds used to treat Candidiasis and Aspergillosis. Comparison and effectiveness of drugs depends upon the infections they are getting affected. Amphotericin B and azole group of drugs are commonly more effective than other group of drugs, but ketoconazole is widely used. Adverse effects of antifungal agents include, skin rashes, irritation, itching, nausea and vomiting, fever, abdominal pain, muscle and joint pain, etc.

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