scholarly journals Effect of β-1,6-Glucan Inhibitors on the Invasion Process of Candida albicans: Potential Mechanism of Their In Vivo Efficacy

2009 ◽  
Vol 53 (9) ◽  
pp. 3963-3971 ◽  
Author(s):  
Akihiro Kitamura ◽  
Saito Higuchi ◽  
Masato Hata ◽  
Katsuhiro Kawakami ◽  
Kumi Yoshida ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Critical Role ◽  
Vaginal Candidiasis ◽  
Specific Cell ◽  
Cell Wall Proteins ◽  
Invasion Process ◽  
In Vivo Efficacy

ABSTRACT β-1,6-Glucan is a fungus-specific cell wall component that is essential for the retention of many cell wall proteins. We recently reported the discovery of a small molecule inhibitor of β-1,6-glucan biosynthesis in yeasts. In the course of our study of its derivatives, we found a unique feature in their antifungal profile. D21-6076, one of these compounds, exhibited potent in vitro and in vivo antifungal activities against Candida glabrata. Interestingly, although it only weakly reduced the growth of Candida albicans in conventional media, it significantly prolonged the survival of mice infected by the pathogen. Biochemical evaluation of D21-6076 indicated that it inhibited β-1,6-glucan synthesis of C. albicans, leading the cell wall proteins, which play a critical role in its virulence, to be released from the cell. Correspondingly, adhesion of C. albicans cells to mammalian cells and their hyphal elongation were strongly reduced by the drug treatment. The results of the experiment using an in vitro model of vaginal candidiasis showed that D21-6076 strongly inhibited the invasion process of C. albicans without a significant reduction in its growth in the medium. These evidences suggested that D21-6076 probably exhibited in vivo efficacy against C. albicans by inhibiting its invasion process.

The fungal-specific subunit i/j of F1FO-ATP synthase stimulates the pathogenicity of Candida albicans independent of oxidative phosphorylation

2020 ◽  
Author(s):  
Yajing Zhao ◽  
Yan Lyu ◽  
Yanli Zhang ◽  
Shuixiu Li ◽  
Yishan Zhang ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
Fungal Infections ◽  
Critical Role ◽  
Antifungal Drug ◽  
F1fo Atp Synthase

Abstract Invasive fungal infections are a major cause of human mortality due in part to a very limited antifungal drug arsenal. The identification of fungal-specific pathogenic mechanisms is considered a crucial step to current antifungal drug development and represents a significant goal to increase the efficacy and reduce host toxicity. Although the overall architecture of F1FO-ATP synthase is largely conserved in both fungi and mammals, the subunit i/j (Su i/j, Atp18) and subunit k (Su k, Atp19) are proteins not found in mammals and specific to fungi. Here, the role of Su i/j and Su k in Candida albicans was characterized by an in vivo assessment of the virulence and in vitro growth and mitochondrial function. Strikingly, the atp18Δ/Δ mutant showed significantly reduced pathogenicity in systemic murine model. However, this substantial defect in infectivity exists without associated defects in mitochondrial oxidative phosphorylation or proliferation in vitro. Analysis of virulence-related traits reveals normal in both mutants, but shows cell wall defects in composition and architecture in the case of atp18Δ/Δ. We also find that the atp18Δ/Δ mutant is more susceptible to attack by macrophages than wild type, which may correlate well with the abnormal cell wall function and increased sensitivity to oxidative stress. In contrast, no significant changes were observed in any of these studies for the atp19Δ/Δ. These results demonstrate that the fungal-specific Su i/j, but not Su k of F1FO-ATP synthase may play a critical role in C. albicans infectivity and represent another opportunity for new therapeutic target investigation. Lay Abstract This study aims to investigate biological functions of fungal-specific subunit i/j and subunit k of ATP synthase in C. albicans oxidative phosphorylation and virulence potential. Our results revealed that subunit i/j, and not subunit k, is critical for C. albicans pathogenicity.

Spilanthol as a promising antifungal alkylamide for the treatment of vulvovaginal candidiasis

2021 ◽  
Author(s):  
Rodrigo L Fabri ◽  
Jhamine C O Freitas ◽  
Ari S O Lemos ◽  
Lara M Campos ◽  
Irley O M Diniz ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Cell Membrane ◽  
Multidrug Resistant ◽  
Fungal Strain ◽  
Vulvovaginal Candidiasis ◽  
Biofilm Matrix

Abstract Spilanthol is a bioactive alkylamide from the native Amazon plant species, Acmella oleracea. However, antifungal activities of spilanthol and its application to the therapeutic treatment of candidiasis remains to be explored. This study sought to evaluate the in vitro and in vivo antifungal activity of spilanthol previously isolated from A. oleracea (spilanthol(AcO)) against Candida albicans ATCC® 10231™, a multidrug-resistant fungal strain. Microdilution methods were used to determine inhibitory and fungicidal concentrations of spilanthol(AcO). In planktonic cultures, the fungal growth kinetics, yeast cell metabolic activity, cell membrane permeability and cell wall integrity were investigated. The effect of spilanthol(AcO) on the proliferation and adhesion of fungal biofilms was evaluated by whole slide imaging and scanning electron microscopy. The biochemical composition of the biofilm matrix was also analyzed. In parallel, spilanthol(AcO) was tested in vivo in an experimental vulvovaginal candidiasis model. Our in vitro analyses in C. albicans planktonic cultures detected a significant inhibitory effect of spilanthol(AcO), which affects both yeast cell membrane and cell wall integrity, interfering with the fungus growth. C. albicans biofilm proliferation and adhesion, as well as, carbohydrates and DNA in biofilm matrix were reduced after spilanthol(AcO) treatment. Moreover, infected rats treated with spilanthol(AcO) showed consistent reduction of both fungal burden and inflammatory processes compared to the untreated animals. Altogether, our findings demonstrated that spilanthol(AcO) is an bioactive compound against planktonic and biofilm forms of a multidrug resistant C. albicans strain. Furthermore, spilanthol(AcO) can be potentially considered for therapeutical treatment of vulvovaginal candidiasis caused by C. albicans. Lay Abstract This study sought to evaluate the antifungal activity of spilanthol against Candida albicans ATCC® 10 231™, a multidrug-resistant fungal strain. Our findings demonstrated that spilanthol(AcO) can be potentially considered for therapeutical treatment of vulvovaginal candidiasis caused by C. albicans.

Cell wall alterations in staphylococci growing in situ in experimental osteomyelitis

1987 ◽  
Vol 33 (2) ◽  
pp. 142-150 ◽  
Author(s):  
J. W. Costerton ◽  
D. W. Lambe Jr. ◽  
K.-J. Mayberry-Carson ◽  
B. Tober-Meyer
Keyword(s):  
Cell Wall ◽  
Cell Size ◽  
Wall Structure ◽  
Specific Cell ◽  
Experimental Osteomyelitis ◽  
Rich Media ◽  
Rabbit Tibia ◽  
Rabbit Bone

When cells of both Staphylococcus aureus and Staphylococcus epidermidis are grown in batch culture in nutrient-rich media, their cell walls are regular in thickness, their cell size is within the normal range for each species, and their septation patterns are orderly. When cells of each of these species are examined directly in infected tissue in the rabbit tibia model infection, their cell wall thickness is often much increased and very irregular around the circumference of the cell, their cell size is often increased, and their septation patterns are often severely deranged. All of these alterations in cell wall structure occur in the absence of antibiotics, and we suggest that they may be an expression of phenotypic plasticity in response to altered environmental conditions such as specific nutrient limitations, the presence of antibacterial factors, and growth of the cells on hard surfaces such as rabbit bone or plastic catheters. Some of these specific cell wall alterations are also seen when staphylococcal cells are exposed, in vitro or in vivo, to antibiotics such as clindamycin, but we emphasize that growth in tissue alone is sufficient for their induction.

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

2006 ◽  
Vol 51 (2) ◽  
pp. 510-520 ◽  
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.

scholarly journals Monoclonal antibodies targeting surface exposed epitopes of Candida albicans cell wall proteins confer in vivo protection in an infection model

2021 ◽  
Author(s):  
Soumya Palliyil ◽  
Mark Mawer ◽  
Sami Alwafi ◽  
Lily Fogg ◽  
Giuseppe Buda De Cesare ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Fungal Infections ◽  
Yeast Cells ◽  
Infection Model ◽  
Cell Wall Proteins ◽  
Peptide Antigens ◽  
Log Reduction ◽  
Pre Treatment

MAb based immunotherapies targeting systemic and deep-seated fungal infections are still in their early stages of development with currently no licensed antifungal mAbs available. The cell wall glycoproteins of Candida albicans are potential targets for therapeutic antibody generation due to their extracellular location and key involvement in fungal pathogenesis. We describe phage display based generation of recombinant human antibodies specifically targeting two key cell wall proteins (CWPs) in C. albicans - Utr2 and Pga31, using peptide antigens representing the surface exposed regions of CWPs at elevated levels during in vivo infection. Reformatted mAbs preferentially recognised C. albicans hyphal forms compared to yeast cells and an increased binding in cells pre-treated with caspofungin. In macrophage interaction assays, mAb pre-treatment resulted in a faster engulfment of C. albicans cells suggesting opsonophagocytosis. Finally, in a series of clinically predictive, mouse models of systemic candidiasis, our lead mAb achieved an improved survival (83%) and several log reduction of fungal burden in the kidneys, similar to levels achieved for the fungicidal drug caspofungin, and superior to any anti-Candida mAb.

LL37 and hBD-3 elevate the β-1,3-exoglucanase activity of Candida albicans Xog1p, resulting in reduced fungal adhesion to plastic

2012 ◽  
Vol 441 (3) ◽  
pp. 963-970 ◽  
Author(s):  
Hao-Teng Chang ◽  
Pei-Wen Tsai ◽  
Hsin-Hui Huang ◽  
Yu-Shu Liu ◽  
Tzu-Shan Chien ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antimicrobial Peptides ◽  
Organ Transplant ◽  
Vaginal Candidiasis ◽  
Immunocompromised Patients ◽  
Fungal Adhesion ◽  
Oral Thrush ◽  
Dose Dependent

The opportunistic fungus Candida albicans causes oral thrush and vaginal candidiasis, as well as candidaemia in immunocompromised patients including those undergoing cancer chemotherapy, organ transplant and those with AIDS. We previously found that the AMPs (antimicrobial peptides) LL37 and hBD-3 (human β-defensin-3) inhibited C. albicans viability and its adhesion to plastic. For the present study, the mechanism by which LL37 and hBD-3 reduced C. albicans adhesion was investigated. After AMP treatment, C. albicans adhesion to plastic was reduced by up to ~60% and was dose-dependent. Our previous study indicated that LL37 might interact with the cell-wall β-1,3-exoglucanase Xog1p, which is involved in cell-wall β-glucan metabolism, and consequently the binding of LL37 or hBD-3 to Xog1p might cause the decrease in adhesion. For the present study, Xog1p(41–438)-6H, an N-terminally truncated, active, recombinant construct of Xog1p and Xog1p fragments were produced and used in pull-down assays and ELISA in vitro, which demonstrated that all constructs interacted with both AMPs. Enzymatic analyses showed that LL37 and hBD-3 enhanced the β-1,3-exoglucanase activity of Xog1p(41–438)-6H approximately 2-fold. Therefore elevated Xog1p activity might compromise cell-wall integrity and decrease C. albicans adhesion. To test this hypothesis, C. albicans was treated with 1.3 μM Xog1p(41–438)-6H and C. albicans adhesion to plastic decreased 47.7%. Taken together, the evidence suggests that Xog1p is one of the LL37/hBD-3 targets, and elevated β-1,3-exoglucanase activity reduces C. albicans adhesion to plastic.

scholarly journals Elevated Cell Wall Chitin in Candida albicans Confers Echinocandin ResistanceIn Vivo

2011 ◽  
Vol 56 (1) ◽  
pp. 208-217 ◽  
Author(s):  
Keunsook K. Lee ◽  
Donna M. MacCallum ◽  
Mette D. Jacobsen ◽  
Louise A. Walker ◽  
Frank C. Odds ◽  
...  
Keyword(s):  
Weight Loss ◽  
Cell Wall ◽  
Candida Albicans ◽  
Point Mutations ◽  
Low Frequency ◽  
Normal Cells ◽  
Content Type ◽  
Echinocandin Resistance

ABSTRACTCandida albicanscells with increased cell wall chitin have reduced echinocandin susceptibilityin vitro. The aim of this study was to investigate whetherC. albicanscells with elevated chitin levels have reduced echinocandin susceptibilityin vivo. BALB/c mice were infected withC. albicanscells with normal chitin levels and compared to mice infected with high-chitin cells. Caspofungin therapy was initiated at 24 h postinfection. Mice infected with chitin-normal cells were successfully treated with caspofungin, as indicated by reduced kidney fungal burdens, reduced weight loss, and decreasedC. albicansdensity in kidney lesions. In contrast, mice infected with high-chitinC. albicanscells were less susceptible to caspofungin, as they had higher kidney fungal burdens and greater weight loss during early infection. Cells recovered from mouse kidneys at 24 h postinfection with high-chitin cells had 1.6-fold higher chitin levels than cells from mice infected with chitin-normal cells and maintained a significantly reduced susceptibility to caspofungin when testedin vitro. At 48 h postinfection, caspofungin treatment induced a further increase in chitin content ofC. albicanscells harvested from kidneys compared to saline treatment. Some of the recovered clones had acquired, at a low frequency, a point mutation inFKS1resulting in a S645Y amino acid substitution, a mutation known to confer echinocandin resistance. This occurred even in cells that had not been exposed to caspofungin. Our results suggest that the efficacy of caspofungin againstC. albicanswas reducedin vivodue to either elevation of chitin levels in the cell wall or acquisition ofFKS1point mutations.

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