scholarly journals Candida albicans Mucin Msb2 Is a Broad-Range Protectant against Antimicrobial Peptides

2013 ◽  
Vol 57 (8) ◽  
pp. 3917-3922 ◽  
Author(s):  
Marc Swidergall ◽  
Andreas M. Ernst ◽  
Joachim F. Ernst
Keyword(s):  
Candida Albicans ◽  
Antimicrobial Peptides ◽  
Tight Binding ◽  
Surface Protein ◽  
Protective Effects ◽  
Content Type ◽  
Histatin 5 ◽  
Growth Environment ◽  
Corynebacterium Pseudodiphtheriticum ◽  
Lipopeptide Antibiotic

ABSTRACTThe human fungal pathogenCandida albicansreleases a large glycofragment of the Msb2 surface protein (Msb2*) into the growth environment, which protects against the action of human antimicrobial peptides (AMPs) LL-37 and histatin-5. Quantitation of Msb2*/LL-37 interactions by microscale thermophoresis revealed high-affinity binding (dissociation constant [KD] = 73 nM), which was lost or greatly diminished by lack ofO-glycosylation or by Msb2* denaturation. Msb2* also interacted with human α- and β-defensins and protectedC. albicansagainst these AMPs. In addition, the lipopeptide antibiotic daptomycin was bound and inactivated by Msb2*, which prevented the killing of bacterial pathogensStaphylococcus aureus,Enterococcus faecalis, andCorynebacterium pseudodiphtheriticum. In coculturings or mixed biofilms ofS. aureuswithC. albicanswild-type but notmsb2mutant strains, the protective effects of Msb2* on the bactericidal action of daptomycin were demonstrated. These results suggest that tight binding of shed Msb2* to AMPs that occurs during bacterial coinfections withC. albicanscompromises antibacterial therapy by inactivating a relevant reserve antibiotic.

scholarly journals Identification and Mechanism of Action of the Plant Defensin NaD1 as a New Member of the Antifungal Drug Arsenal against Candida albicans

2013 ◽  
Vol 57 (8) ◽  
pp. 3667-3675 ◽  
Author(s):  
Brigitte M. E. Hayes ◽  
Mark R. Bleackley ◽  
Jennifer L. Wiltshire ◽  
Marilyn A. Anderson ◽  
Ana Traven ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Osmotic Stress ◽  
Antimicrobial Peptides ◽  
Pathogenic Fungi ◽  
Hog Pathway ◽  
Fungal Cell ◽  
Content Type ◽  
Histatin 5 ◽  
Protection Strategies ◽  
Beta Defensins

ABSTRACTIn recent decades, pathogenic fungi have become a serious threat to human health, leading to major efforts aimed at characterizing new agents for improved treatments. Promising in this context are antimicrobial peptides produced by animals and plants as part of innate immune systems. Here, we describe an antifungal defensin, NaD1, with activity against the major human pathogenCandida albicans, characterize the mechanism of killing, and identify protection strategies used by the fungus to survive defensin treatment. The mechanism involves interaction between NaD1 and the fungal cell surface followed by membrane permeabilization, entry into the cytoplasm, hyperproduction of reactive oxygen species, and killing induced by oxidative damage. By screeningC. albicansmutant libraries, we identified that the high-osmolarity glycerol (HOG) pathway has a unique role in protection against NaD1, while several other stress-responsive pathways are dispensable. The involvement of the HOG pathway is consistent with induction of oxidative stress by NaD1. The HOG pathway has been reported to have a major role in protection of fungi against osmotic stress, but our data indicate that osmotic stress does not contribute significantly to the adverse effects of NaD1 onC. albicans. Our data, together with previous studies with human beta-defensins and salivary histatin 5, indicate that inhibition of the HOG pathway holds promise as a broad strategy for increasing the activity of antimicrobial peptides againstC. albicans.

scholarly journals Candida albicans Cek1 Mitogen-Activated Protein Kinase Signaling Enhances Fungicidal Activity of Salivary Histatin 5

2015 ◽  
Vol 59 (6) ◽  
pp. 3460-3468 ◽  
Author(s):  
Rui Li ◽  
Sumant Puri ◽  
Swetha Tati ◽  
Paul J. Cullen ◽  
Mira Edgerton
Keyword(s):  
Candida Albicans ◽  
Protein Kinase ◽  
Antifungal Drugs ◽  
Mitogen Activated Protein Kinase ◽  
Fungal Cell ◽  
Content Type ◽  
Histatin 5 ◽  
Mitogen Activated Protein ◽  
Hyphal Formation ◽  
Sensor Proteins

ABSTRACTCandida albicansis a major etiological organism for oropharyngeal candidiasis (OPC), while salivary histatin 5 (Hst 5) is a human fungicidal protein that protects the oral cavity from OPC.C. albicanssenses its environment by mitogen-activated protein kinase (MAPK) activation that can also modulate the activity of some antifungal drugs, including Hst 5. We found that phosphorylation of the MAPK Cek1, induced either byN-acetylglucosamine (GlcNAc) or serum, or its constitutive activation by deletion of its phosphatase Cpp1 elevated the susceptibility ofC. albicanscells to Hst 5. Cek1 phosphorylation but not hyphal formation was needed for increased Hst 5 sensitivity. Interference with the Cek1 pathway by deletion of its head sensor proteins, Msb2 and Sho1, or by addition of secreted aspartyl protease (SAP) cleavage inhibitors, such as pepstatin A, reduced Hst 5 susceptibility under Cek1-inducing conditions. Changes in fungal cell surface glycostructures also modulated Hst 5 sensitivity, and Cek1-inducing conditions resulted in a higher uptake rate of Hst 5. These results show that there is a consistent relationship between activation of Cek1 MAPK and increased Hst 5 susceptibility inC. albicans.

scholarly journals The Antimicrobial Peptides P-113Du and P-113Tri Function against Candida albicans

2016 ◽  
Vol 60 (10) ◽  
pp. 6369-6373 ◽  
Author(s):  
Guan-Yu Lin ◽  
Hsueh-Fen Chen ◽  
Yao-Peng Xue ◽  
Ying-Chieh Yeh ◽  
Chia-Lu Chen ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Antimicrobial Peptides ◽  
Antifungal Agents ◽  
Low Ph ◽  
Planktonic Cells ◽  
Content Type ◽  
Peptide Derivatives ◽  
Helix Conformation ◽  
Α Helix

ABSTRACTTwo antimicrobial P-113 peptide derivatives, P-113Du and P-113Tri, were investigated in this study. Notably, P-113Du and P-113Tri contained significant fractions of α-helix conformation and were less sensitive to high salt and low pH than P-113. Moreover, compared to P-113, these peptides exhibited increased antifungal activity against planktonic cells, biofilm cells, and clinical isolates ofCandida albicansand non-albicans Candidaspp. These results suggest that P-113Du and P-113Tri are promising candidates for development as novel antifungal agents.

scholarly journals Candida albicans Als3, a Multifunctional Adhesin and Invasin

2010 ◽  
Vol 10 (2) ◽  
pp. 168-173 ◽  
Author(s):  
Yaoping Liu ◽  
Scott G. Filler
Keyword(s):  
Candida Albicans ◽  
Host Cell ◽  
Surface Protein ◽  
Host Cells ◽  
Content Type ◽  
Multifunctional Protein ◽  
Multiple Functions ◽  
Abiotic Surfaces ◽  
Disseminated Disease

ABSTRACTCandida albicansis part of the normal human flora, and it grows on mucosal surfaces in healthy individuals. In susceptible hosts, this organism can cause both mucosal and hematogenously disseminated disease. ForC. albicansto persist in the host and induce disease, it must be able to adhere to biotic and abiotic surfaces, invade host cells, and obtain iron. TheC. albicanshypha-specific surface protein Als3 is a member of the agglutinin-like sequence (Als) family of proteins and is important in all of these processes. Functioning as an adhesin, Als3 mediates attachment to epithelial cells, endothelial cells, and extracellular matrix proteins. It also plays an important role in biofilm formation on prosthetic surfaces, both alone and in mixed infection withStreptococcus gordonii. Als3 is one of two knownC. albicansinvasins. It binds to host cell receptors such as E-cadherin and N-cadherin and thereby induces host cells to endocytose the organism. Als3 also binds to host cell ferritin and enablesC. albicansto utilize this protein as a source of iron. Because of its multiple functions and its high expression levelin vivo, Als3 is a promising target for vaccines that induce protective cell-mediated and antibody responses. This review will summarize the multiple functions of this interesting and multifunctional protein.

scholarly journals Function of Candida albicans Adhesin Hwp1 in Biofilm Formation

2006 ◽  
Vol 5 (10) ◽  
pp. 1604-1610 ◽  
Author(s):  
Clarissa J. Nobile ◽  
Jeniel E. Nett ◽  
David R. Andes ◽  
Aaron P. Mitchell
Keyword(s):  
Candida Albicans ◽  
Cell Surface ◽  
Biofilm Formation ◽  
Tight Binding ◽  
Surface Protein ◽  
Venous Catheter ◽  
Cell Surface Protein ◽  
Additional Support

ABSTRACT Hwp1 is a well-characterized Candida albicans cell surface protein, expressed only on hyphae, that mediates tight binding to oral epithelial cells. Prior studies indicate that HWP1 expression is dependent upon Bcr1, a key regulator of biofilm formation. Here we test the hypothesis that Hwp1 is required for biofilm formation. In an in vitro model, the hwp1/hwp1 mutant produces a thin biofilm that lacks much of the hyphal mass found in the hwp1/HWP1 reconstituted strain. In a biofilm cell retention assay, we find that the hwp1/hwp1 mutant is defective in retention of nonadherent bcr1/bcr1 mutant cells. In an in vivo rat venous catheter model, the hwp1/hwp1 mutant has a severe biofilm defect, yielding only yeast microcolonies in the catheter lumen. These properties of the hwp1/hwp1 mutant are consistent with its role as a hypha-specific adhesin and indicate that it is required for normal biofilm formation. Overexpression of HWP1 in a bcr1/bcr1 mutant background improves adherence in the in vivo catheter model. This finding provides additional support for the model that Hwp1 is critical for biofilm adhesion. Hwp1 is the first cell surface protein known to be required for C. albicans biofilm formation in vivo and is thus an excellent therapeutic target.

scholarly journals Bcr1 Functions Downstream of Ssd1 To Mediate Antimicrobial Peptide Resistance in Candida albicans

2013 ◽  
Vol 12 (3) ◽  
pp. 411-419 ◽  
Author(s):  
Sook-In Jung ◽  
Jonathan S. Finkel ◽  
Norma V. Solis ◽  
Siyang Chaili ◽  
Aaron P. Mitchell ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Target Genes ◽  
Regulatory Protein ◽  
Homozygous Deletion ◽  
Plasma Membrane Permeability ◽  
Host Defense Peptides ◽  
Content Type ◽  
Antimicrobial Peptide Resistance

ABSTRACTIn order to colonize the host and cause disease,Candida albicansmust avoid being killed by host defense peptides. Previously, we determined that the regulatory protein Ssd1 governs antimicrobial peptide resistance inC. albicans. Here, we sought to identify additional genes whose products govern susceptibility to antimicrobial peptides. We discovered that abcr1Δ/Δ mutant, like thessd1Δ/Δ mutant, had increased susceptibility to the antimicrobial peptides, protamine, RP-1, and human β defensin-2. Homozygous deletion ofBCR1in thessd1Δ/Δ mutant did not result in a further increase in antimicrobial peptide susceptibility. Exposure of thebcr1Δ/Δ andssd1Δ/Δ mutants to RP-1 induced greater loss of mitochondrial membrane potential and increased plasma membrane permeability than with the control strains. Therefore, Bcr1 and Ssd1 govern antimicrobial peptide susceptibility and likely function in the same pathway. Furthermore,BCR1mRNA expression was downregulated in thessd1Δ/Δ mutant, and the forced expression ofBCR1in thessd1Δ/Δ mutant partially restored antimicrobial peptide resistance. These results suggest that Bcr1 functions downstream of Ssd1. Interestingly, overexpression of 11 known Bcr1 target genes in thebcr1Δ/Δ mutant failed to restore antimicrobial peptide resistance, suggesting that other Bcr1 target genes are likely responsible for antimicrobial peptide resistance. Collectively, these results demonstrate that Bcr1 functions downstream of Ssd1 to govern antimicrobial peptide resistance by maintaining mitochondrial energetics and reducing membrane permeabilization.

scholarly journals The Clinical Candidate VT-1161 Is a Highly Potent Inhibitor of Candida albicans CYP51 but Fails To Bind the Human Enzyme

2014 ◽  
Vol 58 (12) ◽  
pp. 7121-7127 ◽  
Author(s):  
A. G. S. Warrilow ◽  
C. M. Hull ◽  
J. E. Parker ◽  
E. P. Garvey ◽  
W. J. Hoekstra ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Potent Inhibitor ◽  
Homo Sapiens ◽  
Tight Binding ◽  
Heme Iron ◽  
Antifungal Compound ◽  
Content Type ◽  
Human Enzyme ◽  
Iron Coordination ◽  
Culture Growth

ABSTRACTThe binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinantCandida albicansCYP51 (ERG11) andHomo sapiensCYP51 were compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum withCandida albicansCYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 forCandida albicansCYP51 was high (dissociation constant [Kd], ≤39 nM) and similar to that of the pharmaceutical azole antifungals (Kd, ≤50 nM). In stark contrast, VT-1161 at concentrations up to 86 μM did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibitedCandida albicansCYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 μM). In addition, VT-1161 (MIC = 0.002 μg ml−1) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC = 0.004 μg ml−1). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibitedCandida albicansCYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment ofCandidainfections.

scholarly journals Candida albicans Flu1-Mediated Efflux of Salivary Histatin 5 Reduces Its Cytosolic Concentration and Fungicidal Activity

2013 ◽  
Vol 57 (4) ◽  
pp. 1832-1839 ◽  
Author(s):  
Rui Li ◽  
Rohitashw Kumar ◽  
Swetha Tati ◽  
Sumant Puri ◽  
Mira Edgerton
Keyword(s):  
Candida Albicans ◽  
Fungicidal Activity ◽  
Threshold Concentration ◽  
Efflux Transporter ◽  
Wild Type ◽  
Intact Cells ◽  
Content Type ◽  
Histatin 5 ◽  
Cellular Processes ◽  
Intracellular Translocation

ABSTRACTHistatin 5 (Hst 5) is a salivary human antimicrobial peptide that is toxic to the opportunistic yeastCandida albicans. Fungicidal activity of Hst 5 requires intracellular translocation and accumulation to a threshold concentration for it to disrupt cellular processes. Previously, we observed that total cytosolic levels of Hst 5 were gradually reduced from intact cells, suggesting thatC. albicanspossesses a transport mechanism for efflux of Hst 5. Since we identifiedC. albicanspolyamine transporters responsible for Hst 5 uptake, we hypothesized that one or more polyamine efflux transporters may be involved in the efflux of Hst 5.C. albicans FLU1andTPO2were found to be the closest homologs ofSaccharomyces cerevisiae TPO1, which encodes a major spermidine efflux transporter, indicating that the products of these two genes may be involved in efflux of Hst 5. We found thatflu1Δ/Δ cells, but nottpo2Δ/Δ cells, had significant reductions in their rates of Hst 5 efflux and had significantly higher cytoplasmic Hst 5 and Hst 5 susceptibilities than did the wild type. We also found thatflu1Δ/Δ cells had reduced biofilm formation compared to wild-type cells in the presence of Hst 5. Transcriptional levels ofFLU1were not altered over the course of treatment with Hst 5; therefore, Hst 5 is not likely to induceFLU1gene overexpression as a potential mechanism of resistance. Thus, Flu1, but not Tpo2, mediates efflux of Hst 5 and is responsible for reduction of its toxicity inC. albicans.

scholarly journals In VitroAnalyses of the Effects of Heparin and Parabens on Candida albicans Biofilms and Planktonic Cells

2011 ◽  
Vol 56 (1) ◽  
pp. 148-153 ◽  
Author(s):  
Marisa H. Miceli ◽  
Stella M. Bernardo ◽  
T. S. Neil Ku ◽  
Carla Walraven ◽  
Samuel A. Lee
Keyword(s):  
Candida Albicans ◽  
Metabolic Activity ◽  
Biofilm Formation ◽  
High Dose ◽  
Dependent Manner ◽  
Planktonic Cells ◽  
Content Type ◽  
Heparin Sodium ◽  
The Individual

ABSTRACTInfections and thromboses are the most common complications associated with central venous catheters. Suggested strategies for prevention and management of these complications include the use of heparin-coated catheters, heparin locks, and antimicrobial lock therapy. However, the effects of heparin onCandida albicansbiofilms and planktonic cells have not been previously studied. Therefore, we sought to determine thein vitroeffect of a heparin sodium preparation (HP) on biofilms and planktonic cells ofC. albicans. Because HP contains two preservatives, methyl paraben (MP) and propyl paraben (PP), these compounds and heparin sodium without preservatives (Pure-H) were also tested individually. The metabolic activity of the mature biofilm after treatment was assessed using XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction and microscopy. Pure-H, MP, and PP caused up to 75, 85, and 60% reductions of metabolic activity of the mature preformedC. albicansbiofilms, respectively. Maximal efficacy against the mature biofilm was observed with HP (up to 90%) compared to the individual compounds (P< 0.0001). Pure-H, MP, and PP each inhibitedC. albicansbiofilm formation up to 90%. A complete inhibition of biofilm formation was observed with HP at 5,000 U/ml and higher. When tested against planktonic cells, each compound inhibited growth in a dose-dependent manner. These data indicated that HP, MP, PP, and Pure-H havein vitroantifungal activity againstC. albicansmature biofilms, formation of biofilms, and planktonic cells. Investigation of high-dose heparin-based strategies (e.g., heparin locks) in combination with traditional antifungal agents for the treatment and/or prevention ofC. albicansbiofilms is warranted.

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