Editorial

2 pages, 209 KiB

Open AccessEditorial

Special Issue: Alternative Therapeutic Approaches of Candida Infections

by Renátó Kovács

J. Fungi 2022, 8(2), 170; https://doi.org/10.3390/jof8020170 - 10 Feb 2022

Viewed by 1155

In recent decades, the prevalence of resistant fungal isolates has been steadily increasing both in veterinary and human medicine as well as in agriculture [...] Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

Research

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22 pages, 5763 KiB

Open AccessArticle

Antifungal Activity of the Phenolic Compounds Ellagic Acid (EA) and Caffeic Acid Phenethyl Ester (CAPE) against Drug-Resistant Candida auris

by Fernanda Cristina Possamai Rossatto, Nagendran Tharmalingam, Iliana E. Escobar, Pedro Alves d’Azevedo, Karine Rigon Zimmer and Eleftherios Mylonakis

J. Fungi 2021, 7(9), 763; https://doi.org/10.3390/jof7090763 - 15 Sep 2021

Cited by 18 | Viewed by 3959

Abstract

Candida auris is an emerging healthcare-associated fungal pathogen that has become a serious global health threat. Current treatment options are limited due to drug resistance. New therapeutic strategies are required to target this organism and its pathogenicity. Plant polyphenols are structurally diverse compounds [...] Read more.

Candida auris is an emerging healthcare-associated fungal pathogen that has become a serious global health threat. Current treatment options are limited due to drug resistance. New therapeutic strategies are required to target this organism and its pathogenicity. Plant polyphenols are structurally diverse compounds that present a vast range of biological properties. In the present study, plant-derived molecules ellagic acid (EA) and caffeic acid phenethyl ester (CAPE) were investigated for their antifungal and antivirulence activities against Candida auris. We also tested against C. albicans. The minimum inhibitory concentration (MIC) for EA ranged from 0.125 to 0.25 µg/mL and for CAPE ranged from 1 to 64 µg/mL against drug-resistant C. auris strains. Killing kinetics determined that after 4 h treatment with CAPE, there was a complete reduction of viable C. auris cells compared to fluconazole. Both compounds might act by modifying the fungal cell wall. CAPE significantly reduced the biomass and the metabolic activity of C. auris biofilm and impaired C. auris adhesion to cultured human epithelial cells. Furthermore, both compounds prolonged the survival rate of Galleria mellonella infected by C. auris (p = 0.0088 for EA at 32 mg/kg and p = 0.0028 for CAPE at 4 mg/kg). In addition, EA at 4 μg/mL prolonged the survival of C. albicans-infected Caenorhabditis elegans (p < 0.0001). CAPE was not able to prolong the survival of C. albicans-infected C. elegans. These findings highlight the antifungal and antivirulence effects of EA and CAPE against C. auris, and warrant further investigation as novel antifungal agents against drug-resistant infections. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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14 pages, 4503 KiB

Open AccessArticle

Eradication of Candida albicans Biofilm Viability: In Vitro Combination Therapy of Cationic Carbosilane Dendrons Derived from 4-Phenylbutyric Acid with AgNO₃ and EDTA

by Natalia Gómez-Casanova, Tania Lozano-Cruz, Juan Soliveri, Rafael Gomez, Paula Ortega, José Luis Copa-Patiño and Irene Heredero-Bermejo

J. Fungi 2021, 7(7), 574; https://doi.org/10.3390/jof7070574 - 18 Jul 2021

Cited by 8 | Viewed by 2602

Abstract

Candida albicans is a human pathogen of significant clinical relevance. This pathogen is resistant to different drugs, and most clinical antifungals are not effective against the prevention and treatment of C. albicans infections. As with other microorganisms, it can produce biofilms that serve [...] Read more.

Candida albicans is a human pathogen of significant clinical relevance. This pathogen is resistant to different drugs, and most clinical antifungals are not effective against the prevention and treatment of C. albicans infections. As with other microorganisms, it can produce biofilms that serve as a barrier against antifungal agents and other substances, contributing to infection in humans and environmental tolerance of this microorganism. Thus, resistances and biofilm formation make treatment difficult. In addition, the complete eradication of biofilms in implants, catheters and other medical devices, is challenging and necessary to prevent relapses of candidemia. Therefore, it is a priority to find new molecules or combinations of compounds with anti-Candida biofilm activity. Due to the difficulty of treating and removing biofilms, the aim of this study was to evaluate the in vitro ability of different generation of cationic carbosilane dendrons derived from 4-phenylbutyric acid, ArCO₂G_n(SNMe₃I)_m, to eradicate C. albicans biofilms. Here, we assessed the antifungal activity of the second generation dendron ArCO2G₂(SNMe₃I)₄ against C. albicans cells and established biofilms since it managed to seriously damage the membrane. In addition, the combinations of the second generation dendron with AgNO₃ or EDTA eradicated the viability of biofilm cells. Alterations were observed by scanning electron microscopy and cytotoxicity was assessed on HeLa cells. Our data suggest that the dendritic compound ArCO₂G₂(SNMe₃I)₄ could represent an alternative to control the infections caused by this pathogen. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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23 pages, 2605 KiB

Open AccessArticle

The Negative Effect of Protein Phosphatase Z1 Deletion on the Oxidative Stress Tolerance of Candida albicans Is Synergistic with Betamethasone Exposure

by Ágnes Jakab, Tamás Emri, Kinga Csillag, Anita Szabó, Fruzsina Nagy, Edina Baranyai, Zsófi Sajtos, Dóra Géczi, Károly Antal, Renátó Kovács, Krisztina Szabó, Viktor Dombrádi and István Pócsi

J. Fungi 2021, 7(7), 540; https://doi.org/10.3390/jof7070540 - 06 Jul 2021

Cited by 5 | Viewed by 2162

Abstract

The glucocorticoid betamethasone (BM) has potent anti-inflammatory and immunosuppressive effects; however, it increases the susceptibility of patients to superficial Candida infections. Previously we found that this disadvantageous side effect can be counteracted by menadione sodium bisulfite (MSB) induced oxidative stress treatment. The fungus [...] Read more.

The glucocorticoid betamethasone (BM) has potent anti-inflammatory and immunosuppressive effects; however, it increases the susceptibility of patients to superficial Candida infections. Previously we found that this disadvantageous side effect can be counteracted by menadione sodium bisulfite (MSB) induced oxidative stress treatment. The fungus specific protein phosphatase Z1 (CaPpz1) has a pivotal role in oxidative stress response of Candida albicans and was proposed as a potential antifungal drug target. The aim of this study was to investigate the combined effects of CaPPZ1 gene deletion and MSB treatment in BM pre-treated C. albicans cultures. We found that the combined treatment increased redox imbalance, enhanced the specific activities of antioxidant enzymes, and reduced the growth in cappz1 mutant (KO) strain. RNASeq data demonstrated that the presence of BM markedly elevated the number of differentially expressed genes in the MSB treated KO cultures. Accumulation of reactive oxygen species, increased iron content and fatty acid oxidation, as well as the inhibiting ergosterol biosynthesis and RNA metabolic processes explain, at least in part, the fungistatic effect caused by the combined stress exposure. We suggest that the synergism between MSB treatment and CaPpz1 inhibition could be considered in developing of a novel combinatorial antifungal strategy accompanying steroid therapy. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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15 pages, 1041 KiB

Open AccessArticle

New Perspectives in the Antimicrobial Activity of the Amphibian Temporin B: Peptide Analogs Are Effective Inhibitors of Candida albicans Growth

by Anant Kakar, Jeanett Holzknecht, Sandrine Dubrac, Maria Luisa Gelmi, Alessandra Romanelli and Florentine Marx

J. Fungi 2021, 7(6), 457; https://doi.org/10.3390/jof7060457 - 07 Jun 2021

Cited by 9 | Viewed by 2778

Abstract

Temporin B (TB) is a short, positively charged peptide secreted by the granular glands of the European frog Rana temporaria. While the antibacterial and antiviral efficacy of TB and some of its improved analogs are well documented, nothing is known about their [...] Read more.

Temporin B (TB) is a short, positively charged peptide secreted by the granular glands of the European frog Rana temporaria. While the antibacterial and antiviral efficacy of TB and some of its improved analogs are well documented, nothing is known about their antifungal potency so far. We dedicated this study to characterize the antifungal potential of the TB analog TB_KKG6K and the newly designed D-Lys_TB_KKG6K, the latter having the L-lysines replaced by the chiral counterpart D-lysines to improve its proteolytic stability. Both peptides inhibited the growth of opportunistic human pathogenic yeasts and killed planktonic and sessile cells of the most prevalent human pathogen, Candida albicans. The anti-yeast efficacy of the peptides coincided with the induction of intracellular reactive oxygen species. Their thermal, cation, pH and serum tolerance were similar, while the proteolytic stability of D-Lys_TB_KKG6K was superior to that of its template peptide. Importantly, both peptides lacked hemolytic activity and showed minimal in vitro cytotoxicity in primary human keratinocytes. The tolerance of both peptides in a reconstructed human epidermis model further supports their potential for topical application. Our results open up an exciting field of research for new anti-Candida therapeutic options based on amphibian TB analogs. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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33 pages, 2967 KiB

Open AccessArticle

Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans—In Silico, In Vitro and In Vivo Approaches

by André L. S. Santos, Lys A. Braga-Silva, Diego S. Gonçalves, Lívia S. Ramos, Simone S. C. Oliveira, Lucieri O. P. Souza, Vanessa S. Oliveira, Roberto D. Lins, Marcia R. Pinto, Julian E. Muñoz, Carlos P. Taborda and Marta H. Branquinha

J. Fungi 2021, 7(6), 424; https://doi.org/10.3390/jof7060424 - 28 May 2021

Cited by 11 | Viewed by 3674

Abstract

The repurposing strategy was applied herein to evaluate the effects of lopinavir, an aspartic protease inhibitor currently used in the treatment of HIV-infected individuals, on the globally widespread opportunistic human fungal pathogen Candida albicans by using in silico, in vitro and in vivo [...] Read more.

The repurposing strategy was applied herein to evaluate the effects of lopinavir, an aspartic protease inhibitor currently used in the treatment of HIV-infected individuals, on the globally widespread opportunistic human fungal pathogen Candida albicans by using in silico, in vitro and in vivo approaches in order to decipher its targets on fungal cells and its antifungal mechanisms of action. Secreted aspartic proteases (Saps) are the obviously main target of lopinavir. To confirm this hypothesis, molecular docking assays revealed that lopinavir bound to the Sap2 catalytic site of C. albicans as well as inhibited the Sap hydrolytic activity in a typically dose-dependent manner. The inhibition of Saps culminated in the inability of C. albicans yeasts to assimilate the unique nitrogen source (albumin) available in the culture medium, culminating with fungal growth inhibition (IC₅₀ = 39.8 µM). The antifungal action of lopinavir was corroborated by distinct microscopy analyses, which evidenced drastic and irreversible changes in the morphology that justified the fungal death. Furthermore, our results revealed that lopinavir was able to (i) arrest the yeasts-into-hyphae transformation, (ii) disturb the synthesis of neutral lipids, including ergosterol, (iii) modulate the surface-located molecules, such as Saps and mannose-, sialic acid- and N-acetylglucosamine-containing glycoconjugates, (iv) diminish the secretion of hydrolytic enzymes, such as Saps and esterase, (v) negatively influence the biofilm formation on polystyrene surface, (vi) block the in vitro adhesion to epithelial cells, (vii) contain the in vivo infection in both immunocompetent and immunosuppressed mice and (viii) reduce the Sap production by yeasts recovered from kidneys of infected animals. Conclusively, the exposed results highlight that lopinavir may be used as a promising repurposing drug against C. albicans infection as well as may be used as a lead compound for the development of novel antifungal drugs. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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17 pages, 2493 KiB

Open AccessArticle

Colombian Essential Oil of Ruta graveolens against Nosocomial Antifungal Resistant Candida Strains

by Matthew Gavino Donadu, Yeimmy Peralta-Ruiz, Donatella Usai, Francesca Maggio, Junior Bernando Molina-Hernandez, Davide Rizzo, Francesco Bussu, Salvatore Rubino, Stefania Zanetti, Antonello Paparella and Clemencia Chaves-Lopez

J. Fungi 2021, 7(5), 383; https://doi.org/10.3390/jof7050383 - 14 May 2021

Cited by 48 | Viewed by 4067

Abstract

Drug resistance in antifungal therapy, a problem unknown until a few years ago, is increasingly assuming importance especially in immunosuppressed patients and patients receiving chemotherapy and radiotherapy. In the past years, the use of essential oils as an approach to improve the effectiveness [...] Read more.

Drug resistance in antifungal therapy, a problem unknown until a few years ago, is increasingly assuming importance especially in immunosuppressed patients and patients receiving chemotherapy and radiotherapy. In the past years, the use of essential oils as an approach to improve the effectiveness of antifungal agents and to reduce antifungal resistance levels has been proposed. Our research aimed to evaluate the antifungal activity of Colombian rue, Ruta graveolens, essential oil (REO) against clinical strains of Candida albicans, Candida parapsilopsis, Candida glabrata, and Candida tropicalis. Data obtained showed that C. tropicalis and C. albicans were the most sensitive strains showing minimum inhibitory concentrations (MIC) of 4.1 and 8.2 µg/mL of REO. Time–kill kinetics assay demonstrated that REO showed a fungicidal effect against C. tropicalis and a fungistatic effect against C. albicans. In addition, an amount of 40% of the biofilm formed by C. albicans was eradicated using 8.2 µg/mL of REO after 1 h of exposure. The synergistic effect of REO together with some antifungal compounds was also investigated. Fractional inhibitory concentration index (FICI) showed synergic effects of REO combined with amphotericin B. REO Lead a disruption in the cellular membrane integrity, consequently resulting in increased intracellular leakage of the macromolecules, thus confirming that the plasma membrane is a target of the mode of action of REO against C. albicans and C. tropicalis. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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14 pages, 2189 KiB

Open AccessArticle

Novel Colloidal Nanocarrier of Cetylpyridinium Chloride: Antifungal Activities on Candida Species and Cytotoxic Potential on Murine Fibroblasts

by Heitor Ceolin Araujo, Laís Salomão Arias, Anne Caroline Morais Caldeirão, Lanay Caroline de Freitas Assumpção, Marcela Grigoletto Morceli, Francisco Nunes de Souza Neto, Emerson Rodrigues de Camargo, Sandra Helena Penha Oliveira, Juliano Pelim Pessan and Douglas Roberto Monteiro

J. Fungi 2020, 6(4), 218; https://doi.org/10.3390/jof6040218 - 12 Oct 2020

Cited by 13 | Viewed by 2307

Abstract

Nanocarriers have been used as alternative tools to overcome the resistance of Candida species to conventional treatments. This study prepared a nanocarrier of cetylpyridinium chloride (CPC) using iron oxide nanoparticles (IONPs) conjugated with chitosan (CS), and assessed its antifungal and cytotoxic effects. CPC [...] Read more.

Nanocarriers have been used as alternative tools to overcome the resistance of Candida species to conventional treatments. This study prepared a nanocarrier of cetylpyridinium chloride (CPC) using iron oxide nanoparticles (IONPs) conjugated with chitosan (CS), and assessed its antifungal and cytotoxic effects. CPC was immobilized on CS-coated IONPs, and the nanocarrier was physico-chemically characterized. Antifungal effects were determined on planktonic cells of Candida albicans and Candida glabrata (by minimum inhibitory concentration (MIC) assays) and on single- and dual-species biofilms of these strains (by quantification of cultivable cells, total biomass and metabolic activity). Murine fibroblasts were exposed to different concentrations of the nanocarrier, and the cytotoxic effect was evaluated by MTT reduction assay. Characterization methods confirmed the presence of a nanocarrier smaller than 313 nm. IONPs-CS-CPC and free CPC showed the same MIC values (0.78 µg mL⁻¹). CPC-containing nanocarrier at 78 µg mL⁻¹ significantly reduced the number of cultivable cells for all biofilms, surpassing the effect promoted by free CPC. For total biomass, metabolic activity, and cytotoxic effects, the nanocarrier and free CPC produced statistically similar outcomes. In conclusion, the IONPs-CS-CPC nanocarrier was more effective than CPC in reducing the cultivable cells of Candida biofilms without increasing the cytotoxic effects of CPC, and may be a useful tool for the treatment of oral fungal infections. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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12 pages, 1210 KiB

Open AccessArticle

Brazilian Copaifera Species: Antifungal Activity against Clinically Relevant Candida Species, Cellular Target, and In Vivo Toxicity

by Géssica Andrade, Haniel Chadwick Silva Orlando, Liliana Scorzoni, Reginaldo Santos Pedroso, Fariza Abrão, Marco Túlio Menezes Carvalho, Rodrigo Cassio Sola Veneziani, Sérgio Ricardo Ambrósio, Jairo Kenupp Bastos, Maria José Soares Mendes-Giannini, Carlos Henrique Gomes Martins and Regina Helena Pires

J. Fungi 2020, 6(3), 153; https://doi.org/10.3390/jof6030153 - 28 Aug 2020

Cited by 12 | Viewed by 2536

Abstract

Plants belonging to the genus Copaifera are widely used in Brazil due to their antimicrobial properties, among others. The re-emergence of classic fungal diseases as a consequence of antifungal resistance to available drugs has stimulated the search for plant-based compounds with antifungal activity, [...] Read more.

Plants belonging to the genus Copaifera are widely used in Brazil due to their antimicrobial properties, among others. The re-emergence of classic fungal diseases as a consequence of antifungal resistance to available drugs has stimulated the search for plant-based compounds with antifungal activity, especially against Candida. The Candida-infected Caenorhabditis elegans model was used to evaluate the in vitro antifungal potential of Copaifera leaf extracts and trunk oleoresins against Candida species. The Copaifera leaf extracts exhibited good antifungal activity against all Candida species, with MIC values ranging from 5.86 to 93.75 µg/mL. Both the Copaifera paupera and Copaifera reticulata leaf extracts at 46.87 µg/mL inhibited Candida glabrata biofilm formation and showed no toxicity to C. elegans. The survival of C. glabrata-infected nematodes increased at all the tested extract concentrations. Exposure to Copaifera leaf extracts markedly increased C. glabrata cell vacuolization and cell membrane damage. Therefore, Copaifera leaf extracts are potential candidates for the development of new and safe antifungal agents. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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Review

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18 pages, 1820 KiB

Open AccessReview

Candida glabrata: Pathogenicity and Resistance Mechanisms for Adaptation and Survival

by Yahaya Hassan, Shu Yih Chew and Leslie Thian Lung Than

J. Fungi 2021, 7(8), 667; https://doi.org/10.3390/jof7080667 - 17 Aug 2021

Cited by 54 | Viewed by 11091

Abstract

Candida glabrata is a yeast of increasing medical relevance, particularly in critically ill patients. It is the second most isolated Candida species associated with invasive candidiasis (IC) behind C. albicans. The attributed higher incidence is primarily due to an increase in the [...] Read more.

Candida glabrata is a yeast of increasing medical relevance, particularly in critically ill patients. It is the second most isolated Candida species associated with invasive candidiasis (IC) behind C. albicans. The attributed higher incidence is primarily due to an increase in the acquired immunodeficiency syndrome (AIDS) population, cancer, and diabetic patients. The elderly population and the frequent use of indwelling medical devices are also predisposing factors. This work aimed to review various virulence factors that facilitate the survival of pathogenic C. glabrata in IC. The available published research articles related to the pathogenicity of C. glabrata were retrieved and reviewed from four credible databases, mainly Google Scholar, ScienceDirect, PubMed, and Scopus. The articles highlighted many virulence factors associated with pathogenicity in C. glabrata, including adherence to susceptible host surfaces, evading host defences, replicative ageing, and producing hydrolytic enzymes (e.g., phospholipases, proteases, and haemolysins). The factors facilitate infection initiation. Other virulent factors include iron regulation and genetic mutations. Accordingly, biofilm production, tolerance to high-stress environments, resistance to neutrophil killings, and development of resistance to antifungal drugs, notably to fluconazole and other azole derivatives, were reported. The review provided evident pathogenic mechanisms and antifungal resistance associated with C. glabrata in ensuring its sustenance and survival. Full article

(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections)

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