scholarly journals Liposomes functionalized with fungi-targeting peptide demonstrate increased interaction with Candida albicans

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Ronnie LaMastro ◽  
Noel Vera-Gonzalez ◽  
Kayla Campbell ◽  
Anita Shukla
Keyword(s):  
Candida Albicans ◽  
Water Solubility ◽  
Solid Phase ◽  
Fungal Infections ◽  
Solid Phase Peptide Synthesis ◽  
Antifungal Drugs ◽  
Histatin 5 ◽  
Delivery Platform ◽  
Targeting Peptide ◽  
Nih 3T3

Candida albicans infections can be challenging to treat, as current antifungal drugs exhibit poor water solubility and host toxicity. To overcome these issues, new methods of drug delivery are needed. Liposomes have been shown to be an effective method for administrating antifungals and can increase bioavailability and solubility while decreasing toxicity. However, existing antifungal liposomal formulations lack infection specificity. For example, AmBisome, a liposomal formulation of amphotericin B, relies on passive accumulation to infection sites. We have developed antifungal liposomes that display fungi-targeting moieties to promote interaction with Candida;we predict that these formulations can increase fungal eradication and decrease off-site toxicity. Here, the C. albicans-targeting peptide P-113Q2.10 (AQRHHGYKRQFH), a derivative of the antifungal peptide histatin 5, was incorporated into liposomes via conjugation to palmitic acid (PA). PA-P-113Q2.10 conjugates were synthesized using solid phase peptide synthesis, confirmed by liquid-chromatography-mass spectrometry. Liposomes composed of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine and cholesterol with 1% w/w PA-P-113Q2.10 were formed via thin film-hydration and extrusion, yielding ∼100 nm liposomes with a polydispersity index of ∼0.1. Flow cytometry demonstrated that interaction with C. albicans SC5314 was enhanced for P-113Q2.10 liposomes, increasing from ∼60% in cells incubated with liposomes lacking peptide to ∼79%. These liposomes preferentially interact with C. albicans compared to NIH 3T3 murine fibroblasts; on average, only ∼15% of fibroblasts incubated with liposomes (with and without peptide) showed positive liposome interaction. This liposome formulation has the potential to serve as an antifungal delivery platform that selectively targets C. albicans cells for increased efficacy in treatment of fungal infections.

Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
Author(s):  
Manzoor Ahmad Malik ◽  
Shabir Ahmad Lone ◽  
Parveez Gull ◽  
Ovas Ahmad Dar ◽  
Mohmmad Younus Wani ◽  
...  
Keyword(s):  
Schiff Base ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Infections ◽  
Total Sterol ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Ergosterol Biosynthesis ◽  
Dependent Manner ◽  
Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

scholarly journals Whole-Genome Approach to Understanding the Mechanism of Action of a Histatin 5-Derived Peptide

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Cody B. Bullock ◽  
David S. McNabb ◽  
Inés Pinto
Keyword(s):  
Mechanism Of Action ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Content Type ◽  
Histatin 5 ◽  
Amino Acid Peptide ◽  
Killing Activity ◽  
Transport Chain ◽  
Mitochondrial Functions ◽  
Increased Sensitivity

ABSTRACT The incidence of opportunistic fungal infections that threaten immunocompromised patients, along with the limited arsenal of antifungal drugs, calls for renewed efforts to develop novel antifungal therapies. Antimicrobial peptides have garnered interest as potential therapeutics. Among naturally occurring peptides, histatin 5 is a well-characterized 24-amino-acid peptide with strong antifungal activity. Our lab has identified a smaller histatin derivative, KM29, with stronger activity against multiple Candida spp., prompting us to investigate its fungicidal mechanism. A genetic screen was developed to test the Saccharomyces cerevisiae genomewide deletion collection for mutants with increased or decreased peptide sensitivity. The goal was to identify genes that would reveal insights into the mechanism of action of KM29, to be assessed in Candida albicans. Several biological processes yielded increased sensitivity, with endosomal transport and vacuolar function appearing at high frequencies. Among the pathways involved in increased resistance, mitochondrial function showed the highest normalized genome frequency; hence, we focused on characterizing this pathway. KM29 localizes to mitochondria, and the killing activity depends on a functional electron transport chain. In addition, KM29 triggered reactive oxygen species (ROS) production, which was responsible for some cell death but insufficient to account for the complete killing activity. In agreement with this finding, we found that KM29 induced mitochondrial fragmentation and a mild loss of mitochondrial membrane potential. Furthermore, respiratory mutants exhibited severely diminished KM29 uptake. We confirmed this behavior in a C. albicans respiratory mutant. Taking our findings together, this work delineates the mitochondrial functions associated with KM29 fungicidal activity and provides additional pathways for further characterization in Candida spp.

scholarly journals A New Form of Intraoral Delivery of Antifungal Drugs for the Treatment of Denture-Induced Oral Candidosis

2009 ◽  
Vol 03 (04) ◽  
pp. 257-266 ◽  
Author(s):  
Wala M. Amin ◽  
Muna H. Al-Ali ◽  
Nesreen A. Salim ◽  
Sandra K. Al-Tarawneh
Keyword(s):  
Candida Albicans ◽  
Methyl Methacrylate ◽  
Fungal Infections ◽  
Ultra Violet ◽  
Antifungal Drugs ◽  
Distilled Water ◽  
Clinical Value ◽  
Sustained Drug Release ◽  
Poly Methyl Methacrylate ◽  
Pmma Resin

ABSTRACTObjectives: To monitor the release of the antifungal drugs Fluconazole, Chlorhexidine and a combination of the two from an auto-polymerized poly (methyl methacrylate) (PMMA) denture base resin; and to investigate the effect of the released drugs upon the growth of Candida albicans.Methods: A high performance liquid chromatography-Ultra violet (HPLC-UV) method was used in the analysis of the released drugs into distilled water from PMMA discs doped with the antifungal drugs Fluconazole (10%), Chlorhexidine (10%) and a combination of the two drugs (5% each). The antifungal efficacy of the released drugs was monitored, microbiologically, employing “well” technique on a Saborauds culture medium inoculated with a resistant strain of Candida albicans.Results: It was shown that Fluconazole, Chlorhexidine and the combination of the two drugs can be successfully incorporated with PMMA. It was found that the drugs leach steadily out of the PMMA resin into distilled water at mouth temperature and that sustained drug release continued throughout the 28 days test period. It was also shown that the released drugs demonstrated an antifungal activity against the resistant Candida albicans and this was most remarkable in the combined drugs samples.Conclusions: The findings of this investigation have a clinical value in terms of their significant contribution to the treatment of fungal infections of the oral cavity. The sustained release of antifungal drugs from the PMMA resin clearly constitutes a new dosage form of these drugs via the poly (methyl methacrylate) delivery system. (Eur J Dent 2009;3:257-266)

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 BAR Domain Proteins Rvs161 and Rvs167 Contribute to Candida albicans Endocytosis, Morphogenesis, and Virulence

2009 ◽  
Vol 77 (9) ◽  
pp. 4150-4160 ◽  
Author(s):  
Lois M. Douglas ◽  
Stephen W. Martin ◽  
James B. Konopka
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Plasma Membrane ◽  
Antifungal Drugs ◽  
Host Immune System ◽  
Membrane Function ◽  
Histatin 5 ◽  
Essentially Normal ◽  
Altered Cell

ABSTRACT The Candida albicans plasma membrane plays critical roles in growth and virulence and as a target for antifungal drugs. Three C. albicans genes that encode Bin-Amphiphysin-Rvs homology domain proteins were mutated to define their roles in plasma membrane function. The deletion of RVS161 and RVS167, but not RVS162, caused strong defects. The rvs161Δ mutant was more defective in endocytosis and morphogenesis than rvs167Δ, but both were strongly defective in polarizing actin patches. Other plasma membrane constituents were still properly localized, including a filipin-stained domain at the hyphal tips. An analysis of growth under different in vitro conditions showed that the rvs161Δ and rvs167Δ mutants grew less invasively in agar and also suggested that they have defects in cell wall synthesis and Rim101 pathway signaling. These mutants were also more resistant to the antimicrobial peptide histatin 5 but showed essentially normal responses to the drugs caspofungin and amphotericin. Surprisingly, the rvs161Δ mutant was more sensitive to fluconazole, whereas the rvs167Δ mutant was more resistant, indicating that these mutations cause overlapping but distinct effects on cells. The rvs161Δ and rvs167Δ mutants both showed greatly reduced virulence in mice. However, the mutants were capable of growing to high levels in kidneys. Histological analyses of infected kidneys revealed that these rvsΔ mutants grew in a large fungal mass that was walled off by leukocytes, rather than forming disseminated microabscesses as seen for the wild type. The diminished virulence is likely due to a combination of the morphogenesis defects that reduce invasive growth and altered cell wall construction that exposes proinflammatory components to the host immune system.

scholarly journals The Effects of Tormentic Acid and Extracts from Callistemon citrinus on Candida albicans and Candida tropicalis Growth and Inhibition of Ergosterol Biosynthesis in Candida albicans

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Chido Bvumbi ◽  
Godloves Fru Chi ◽  
Marc Y. Stevens ◽  
Molly Mombeshora ◽  
Stanley Mukanganyama
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Candida Tropicalis ◽  
Methanol Extract ◽  
Fungal Infections ◽  
Water Extract ◽  
Antifungal Drugs ◽  
Ergosterol Content ◽  
Broth Microdilution Method ◽  
Tormentic Acid

Candida albicans and Candida tropicalis are the leading causes of human fungal infections worldwide. There is an increase in resistance of Candida pathogens to existing antifungal drugs leading to a need to find new sources of antifungal agents. Tormentic acid has been isolated from different plants including Callistemon citrinus and has been found to possess antimicrobial properties, including antifungal activity. The study aimed to determine the effects of tormentic and extracts from C. citrinus on C. albicans and C. tropicalis and a possible mode of action. The extracts and tormentic acid were screened for antifungal activity using the broth microdilution method. The growth of both species was inhibited by the extracts, and C. albicans was more susceptible to the extract compared to C. tropicalis. The growth of C. albicans was inhibited by 80% at 100 μg/ml of both the DCM: methanol extract and the ethanol: water extract. Tormentic acid reduced the growth of C. albicans by 72% at 100 μg/ml. The effects of the extracts and tormentic acid on ergosterol content in C. albicans were determined using a UV/Vis scanning spectrophotometer. At concentrations of tormentic acid of 25 μg/ml, 50 μg/ml, 100 μg/ml, and 200 μg/ml, the content of ergosterol was decreased by 22%, 36%, 48%, and 78%, respectively. Similarly, the DCM: methanol extract at 100 μg/ml and 200 μg/ml decreased the content by 78% and 88%, respectively. A dose-dependent decrease in ergosterol content was observed in cells exposed to miconazole with a 25 μg/ml concentration causing a 100% decrease in ergosterol content. Therefore, tormentic acid inhibits the synthesis of ergosterol in C. albicans. Modifications of the structure of tormentic acid to increase its antifungal potency may be explored in further studies.

scholarly journals Effects ofMentha suaveolensEssential Oil Alone or in Combination with Other Drugs inCandida albicans

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Annarita Stringaro ◽  
Elisabetta Vavala ◽  
Marisa Colone ◽  
Federico Pepi ◽  
Giuseppina Mignogna ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Candida Albicans ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Yeast Cells ◽  
Cellular Damage ◽  
Prolonged Treatment ◽  
Microbial Biofilms ◽  
Transmission Electron ◽  
Morphological Differences

Candidosis is the most important cause of fungal infections in humans. The yeastCandida albicanscan form biofilms, and it is known that microbial biofilms play an important role in human diseases and are very difficult to treat. The prolonged treatment with drugs has often resulted in failure and resistance. Due to the emergence of multidrug resistance, alternatives to conventional antimicrobial therapy are needed. This study aims to analyse the effects induced by essential oil ofMentha suaveolensEhrh (EOMS) onCandida albicansand its potential synergism when used in combination with conventional drugs. Morphological differences between control and EOMS treated yeast cells or biofilms were observed by scanning electron microscopy and transmission electron microscopy (SEM and TEM resp.,). In order to reveal the presence of cell cycle alterations, flow cytometry analysis was carried out as well. The synergic action of EOMS was studied with the checkerboard method, and the cellular damage induced by different treatments was analysed by TEM. The results obtained have demonstrated both the effects of EOMS onC. albicansyeast cells and biofilms and the synergism of EOMS when used in combination with conventional antifungal drugs as fluconazole (FLC) and micafungin (MCFG), and therefore we can hypothesize on its potential use in therapy. Further studies are necessary to know its mechanism of action.

scholarly journals Visible Lights Combined with Photosensitizing Compounds Are Effective against Candida albicans Biofilms

2021 ◽  
Vol 9 (3) ◽  
pp. 500 ◽  
Author(s):  
Priyanka Bapat ◽  
Gurbinder Singh ◽  
Clarissa J. Nobile
Keyword(s):  
Candida Albicans ◽  
Photodynamic Therapy ◽  
Biofilm Formation ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Antifungal Drugs ◽  
Clinical Settings ◽  
Drug Resistant ◽  
Candida Albicans Biofilms

Fungal infections are increasing in prevalence worldwide, especially in immunocompromised individuals. Given the emergence of drug-resistant fungi and the fact that there are only three major classes of antifungal drugs available to treat invasive fungal infections, there is a need to develop alternative therapeutic strategies effective against fungal infections. Candida albicans is a commensal of the human microbiota that is also one of the most common fungal pathogens isolated from clinical settings. C. albicans possesses several virulence traits that contribute to its pathogenicity, including the ability to form drug-resistant biofilms, which can make C. albicans infections particularly challenging to treat. Here, we explored red, green, and blue visible lights alone and in combination with common photosensitizing compounds for their efficacies at inhibiting and disrupting C. albicans biofilms. We found that blue light inhibited biofilm formation and disrupted mature biofilms on its own and that the addition of photosensitizing compounds improved its antibiofilm potential. Red and green lights, however, inhibited biofilm formation only in combination with photosensitizing compounds but had no effects on disrupting mature biofilms. Taken together, these results suggest that photodynamic therapy may be an effective non-drug treatment for fungal biofilm infections that is worthy of further exploration.

scholarly journals Candida albicans hyphal expansion causes phagosomal membrane damage and luminal alkalinization

2018 ◽  
Author(s):  
Johannes Westman ◽  
Gary Moran ◽  
Selene Mogavero ◽  
Bernhard Hube ◽  
Sergio Grinstein
Keyword(s):  
Candida Albicans ◽  
Fungal Infections ◽  
Membrane Damage ◽  
Hyphal Growth ◽  
Antifungal Drugs ◽  
Apparent Paradox ◽  
Opportunistic Fungi ◽  
Life Threatening ◽  
Proton Leakage ◽  
Phagosomal Membrane

ABSTRACTMacrophages rely on phagosomal acidity to destroy engulfed microorganisms. To survive this hostile response, opportunistic fungi such as Candida albicans developed strategies to evade the acidic environment. C. albicans is polymorphic, able to convert from yeast to hyphae, and this transition is required to subvert the microbicidal activity of the phagosome. However, the phagosomal lumen, which is acidic and nutrient-deprived, inhibits yeast-to-hypha transition. To account for this apparent paradox, it was recently proposed that C. albicans produces ammonia that alkalinizes the phagosome, thus facilitating yeast-to-hypha transformation. We re-examined the mechanism underlying phagosomal alkalinization by applying dual-wavelength ratiometric pH measurements. The phagosomal membrane was found to be highly permeable to ammonia, which is therefore unlikely to account for the pH elevation. Instead, we find that yeast-to-hypha transition begins within acidic phagosomes, and that alkalinization is a consequence of proton leakage induced by excessive membrane distension caused by the expanding hypha.IMPORTANCEC. albicans is the most common nosocomial fungal infection, and over three million people acquire life-threatening invasive fungal infections every year. Even if antifungal drugs exist, almost half of these patients will die. Despite this, fungi remain underestimated as pathogens. Our study uses quantitative biophysical approaches to demonstrate that the yeast-to-hypha transition occurs within the nutrient deprived, acidic phagosome and that alkalinization is a consequence, as opposed to the cause of hyphal growth.

Recent Advances in Azole Based Scaffolds as Anticandidal Agents

2019 ◽  
Vol 16 (5) ◽  
pp. 492-501 ◽  
Author(s):  
Prabhuodeyara Math Gurubasavaraj ◽  
Jasmith Shivayya Charantimath
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Drug Interactions ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Virulence ◽  
Compromised Patients

Aim:The present review aims to explore the development of novel antifungal agents, such as pharmacology, pharmacokinetics, spectrum of activity, safety, toxicity and other aspects that involve drug-drug interactions of the azole antifungal agents.Introduction:Fungal infections in critically ill and immune-compromised patients are increasing at alarming rates, caused mainly by Candida albicans an opportunistic fungus. Despite antifungal annihilators like amphotericin B, azoles and caspofungin, these infections are enormously increasing. The unconventional increase in such patients is a challenging task for the management of antifungal infections especially Candidiasis. Moreover, problem of toxicity associated with antifungal drugs on hosts and rise of drug-resistance in primary and opportunistic fungal pathogens has obstructed the success of antifungal therapy.Conclusion:Hence, to conflict these problems new antifungal agents with advanced efficacy, new formulations of drug delivery and novel compounds which can interact with fungal virulence are developed and used to treat antifungal infections.

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