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Antifungal Discovery of Natural Products

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A special issue of Journal of Fungi (ISSN 2309-608X).

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 20071

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Dr. Maria Elisa Rodrigues

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Guest Editor

CEB-Centre of Biological Engineering, University of Minho, 4710-057 Braga, Portugal
Interests: candida; antifungal agent; fungal infection; biofilm
Special Issues, Collections and Topics in MDPI journals

Dr. Sónia Silva

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Guest Editor

1. I.P – National Institute for Agrarian and Veterinarian Research (INIAV), Vairão, Portugal
2. Centre of Biological Engineering (CEB), Laboratory of Research in Biofilms Rosário Oliveira (LIBRO), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
3. LABBELS–Associate Laboratory, Braga/Guimarães, Portugal
Interests: food microbiology; pet animal infections; medical biotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fungal infections are commonly treated with antifungal drugs, mainly belonging to the azoles, polyenes and echinocandins classes. However, most of these synthetic antifungal agents present several disadvantages in terms of toxicity, intensity of side effects, drug interactions, lack of fungicidal efficacy, high costs and inducing of resistance on clinical isolates caused by prolonged therapies. Therefore, the development of more effective alternative treatments with fewer human health disadvantages is crucial. The use of natural products for the control of fungicidal diseases has been considered an interesting alternative to synthetic fungicides, presenting several advantages (lower costs; absence of adverse reactions; easy access; application to several pathologies; less negative impact on individual health; low resistance induction). Therefore, natural products are an excellent source of substances that can be used in the formulation of new antifungal agents, being a natural alternative for antimicrobial therapy, thus avoiding synthetic antifungal therapy which has been excessive in recent years.

Dr. Maria Elisa Rodrigues
Dr. Sónia Silva
Guest Editors

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Keywords

natural products
antifungal effect
antimicrobial resistance
fungal infections
derivatives from plants
bioactive components

Published Papers (9 papers)

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Research

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17 pages, 2612 KiB

Open AccessArticle

Lippia origanoides Essential Oil or Thymol in Combination with Fluconazole Produces Damage to Cells and Reverses the Azole-Resistant Phenotype of a Candida tropicalis Strain

by Carolina Zapata-Zapata, Mauricio Rojas-López, Liliana T. García, Wendy Quintero, María C. Terrón, Daniel Luque and Ana C. Mesa-Arango

J. Fungi 2023, 9(9), 888; https://doi.org/10.3390/jof9090888 - 30 Aug 2023

Cited by 2 | Viewed by 981

Abstract

Candida tropicalis is one of the most pathogenic species within the genus. Increased antifungal resistance has been reported, which is in part due to the organism’s ability to form biofilms. In natural products derived from plants, such as essential oils (EOs) or their major components, there is significant potential to develop new antifungals or to both enhance the efficacy and reduce the toxicity of conventional antifungals. This study aimed to evaluate the effect of combining an EO of Lippia origanoides or thymol with fluconazole on an azole-resistant C. tropicalis strain. Synergism was observed in the combination of fluconazole with the EO and with thymol, and minimal inhibitory concentrations for fluconazole decreased at least 32-fold. As a consequence of the synergistic interactions, mitochondrial membrane potential was reduced, and mitochondrial superoxide production increased. Alteration in nuclear morphology, cell surface, and ultrastructure was also observed. In conclusion, the synergistic interaction between L. origanoides EO or thymol with fluconazole reverted the azole-resistant C. tropicalis phenotype. These findings suggest that L. origanoides EO or thymol alone, or in combination with fluconazole, have the potential for development as antifungal therapies for this yeast, including resistant strains. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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15 pages, 3669 KiB

Open AccessArticle

In Vitro and In Vivo Activity of Citral in Combination with Amphotericin B, Anidulafungin and Fluconazole against Candida auris Isolates

by Iñigo de-la-Fuente, Andrea Guridi, Nerea Jauregizar, Elena Eraso, Guillermo Quindós and Elena Sevillano

J. Fungi 2023, 9(6), 648; https://doi.org/10.3390/jof9060648 - 06 Jun 2023

Viewed by 1358

Abstract

Candida auris is an emerging fungal pathogen responsible for hospital outbreaks of invasive candidiasis associated with high mortality. The treatment of these mycoses is a clinical challenge due to the high resistance levels of this species to current antifungal drugs, and alternative therapeutic strategies are needed. In this study, we evaluated the in vitro and in vivo activities of combinations of citral with anidulafungin, amphotericin B or fluconazole against 19 C. auris isolates. The antifungal effect of citral was in most cases similar to the effect of the antifungal drugs in monotherapy. The best combination results were obtained with anidulafungin, with synergistic and additive interactions against 7 and 11 of the 19 isolates, respectively. The combination of 0.06 μg/mL anidulafungin and 64 μg/mL citral showed the best results, with a survival rate of 63.2% in Caenorhabditis elegans infected with C. auris UPV 17-279. The combination of fluconazole with citral reduced the MIC of fluconazole from > 64 to 1–4 μg/mL against 12 isolates, and a combination of 2 μg/mL fluconazole and 64 μg/mL citral was also effective in reducing mortality in C. elegans. Amphotericin B combined with citral, although effective in vitro, did not improve the activity of each compound in vivo. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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12 pages, 2195 KiB

Open AccessArticle

Case of Mixed Infection of Toenail Caused by Candida parapsilosis and Exophiala dermatitidis and In Vitro Effectiveness of Propolis Extract on Mixed Biofilm

by Alana Salvador, Flávia Franco Veiga, Terezinha Inez Estivalet Svidzinski and Melyssa Negri

J. Fungi 2023, 9(5), 581; https://doi.org/10.3390/jof9050581 - 17 May 2023

Cited by 2 | Viewed by 1568

Abstract

Onychomycosis is a chronic fungal nail infection caused by several filamentous and yeast-like fungi, such as the genus Candida spp., of great clinical importance. Black yeasts, such as Exophiala dermatitidis, a closely related Candida spp. species, also act as opportunistic pathogens. Fungi infectious diseases are affected by organisms organized in biofilm in onychomycosis, making treatment even more difficult. This study aimed to evaluate the in vitro susceptibility profile to propolis extract and the ability to form a simple and mixed biofilm of two yeasts isolated from the same onychomycosis infection. The yeasts isolated from a patient with onychomycosis were identified as Candida parapsilosis sensu stricto and Exophiala dermatitidis. Both yeasts were able to form simple and mixed (in combination) biofilms. Notably, C. parapsilosis prevailed when presented in combination. The susceptibility profile of propolis extract showed action against E. dermatitidis and C. parapsilosis in planktonic form, but when the yeasts were in mixed biofilm, we only observed action against E. dermatitidis, until total eradication. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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12 pages, 2440 KiB

Open AccessArticle

Insight into the Antifungal Effects of Propolis and Carnosic Acid—Extension to the Pathogenic Yeast Candida glabrata: New Propolis Fractionation and Potential Synergistic Applications

by Alejandra Argüelles, Ruth Sánchez-Fresneda, José P. Guirao-Abad, José Antonio Lozano, Francisco Solano and Juan-Carlos Argüelles

J. Fungi 2023, 9(4), 442; https://doi.org/10.3390/jof9040442 - 04 Apr 2023

Cited by 3 | Viewed by 1444

Abstract

Fungi have traditionally been considered opportunistic pathogens in primary infections caused by virulent bacteria, protozoan, or viruses. Consequently, antimycotic chemotherapy is clearly less developed in comparison to its bacterial counterpart. Currently, the three main families of antifungals (polyenes, echinocandins, and azoles) are not sufficient to control the enormous increase in life-threatening fungal infections recorded in recent decades. Natural substances harvested from plants have traditionally been utilized as a successful alternative. After a wide screening of natural agents, we have recently obtained promising results with distinct formulations of carnosic acid and propolis on the prevalent fungal pathogens Candida albicans and Cryptococcus neoformans. Here, we extended their use to the treatment against the emerging pathogenic yeast Candida glabrata, which displayed lower susceptibility in comparison to the fungi mentioned above. Taking into account the moderate antifungal activity of both natural agents, the antifungal value of these combinations has been improved through the obtention of the hydroethanolic fractions of propolis. In addition, we have demonstrated the potential clinical application of new therapeutical designs based on sequential pre-treatments with carnosic/propolis mixtures, followed by exposure to amphotericin B. This approach increased the toxic effect induced by this polyene. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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13 pages, 4311 KiB

Open AccessArticle

Antifungal Activity of 6-Methylcoumarin against Valsa mali and Its Possible Mechanism of Action

by Yun-Ze Chen, Shu-Ren Wang, Tao Li, Guo-Cai Zhang and Jing Yang

J. Fungi 2023, 9(1), 5; https://doi.org/10.3390/jof9010005 - 20 Dec 2022

Cited by 6 | Viewed by 1431

Abstract

Valsa canker of apple (VCA) caused by Valsa mali severely affected apple production in east Asia. With the increase in drug resistance, there is an urgent need for efficient and environmentally friendly antifungal agents. Coumarins have attracted much attention due to their excellent antimicrobial activity against plant pathogens. In this study, the antifungal activity of several coumarins against phytopathogenic fungi was evaluated, and then the antifungal activity of the screened 6-MCM against V. mali and its underlying mechanism was further investigated. The results of the in vitro antifungal activity assay showed that some coumarins had significant inhibitory effects on V. mali. Notably, 400 mg/L of 6-MCM had the best antifungal activity of 94.6%. Further experiments showed that 6-MCM slowed down the growth of V. mali mycelia and the germination of spores in a concentration-dependent manner, with EC₅₀ of 185.49 and 54.62 mg/L, respectively. In addition, 6-MCM treatment increased mycelial conductivity, extracellular protein leakage, and MDA content, resulting in damage to the cell membrane. Moreover, 6-MCM significantly reduced the cell wall degrading enzymes secreted by V. mali, including EG, PG and PL, thereby limiting its pathogenic capacity. SEM and TEM results showed that 6-MCM treatment had a significant effect on the morphology and ultrastructure of mycelial cells. Inoculation of isolated apple branches found that the application of 6-MCM effectively inhibited the development of VCA and significantly reduced the incidence. All these results suggest that 6-MCM has the potential as a green substitute for VCA control. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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17 pages, 2501 KiB

Open AccessArticle

Screening, and Optimization of Fermentation Medium to Produce Secondary Metabolites from Bacillus amyloliquefaciens, for the Biocontrol of Early Leaf Spot Disease, and Growth Promoting Effects on Peanut (Arachis hypogaea L.)

by Taswar Ahsan, Chaoqun Zang, Shuyi Yu, Xue Pei, Jinhui Xie, Ying Lin, Xiaozhou Liu and Chunhao Liang

J. Fungi 2022, 8(11), 1223; https://doi.org/10.3390/jof8111223 - 20 Nov 2022

Cited by 3 | Viewed by 2026

Abstract

A novel Bacillus amyloliquefaciens BAM strain, with novel fermentation nutrient mediums and compositions, could produce potent antifungal secondary metabolites, as the existing strains face resistance from fungus pathogens. In the current study, we introduced two novel nutrient mediums for the fermentation process, semolina and peanut root extract, as carbon and nitrogen sources in order to maximize the antifungal effects of B. amyloliquefaciens against Cercaspora arachidichola to control early leaf spot disease in peanuts. Based on a single-factor test and the central composite design of response surface methodology, the optimum fermentation medium for Bacillus amyloliquefaciens antagonistic substance was determined, containing 15 gm/L of semolina flour, 12.5 gm/L of beef extract, and 0.5 gm/L of magnesium sulfate, which inhibited the fungal growth by 91%. In vitro, antagonistic activity showed that the fermentation broth of B. amyloliquefaciens BAM with the optimized medium formulation had an inhibition rate of (92.62 ± 2.07)% on the growth of C. arachidichola. Disease control effects in pot experiments show that the pre-infection spray of B. amyloliquefaciens BAM broth had significant efficiency of (92.00 ± 3.79)% in comparison to post-infection spray. B. amyloliquefaciens BAM broth significantly promoted peanut plant growth and physiological parameters and reduced the biotic stress of C. archidechola. Studies revealed that B. amyloliquefaciens BAM with a novel fermentation formulation could be an ideal biocontrol and biofertilizer agent and help in early disease management of early leaf spots in peanuts. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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16 pages, 2132 KiB

Open AccessArticle

γ-Cyclodextrin-Encapsulated Cinnamaldehyde for Citrus Preservation and Its Potential Mechanisms against Penicillium digitatum

by Yonghua Zhang, Yuanzhen Tan, Okwong Oketch Reymick, Qiuli Ouyang and Nengguo Tao

J. Fungi 2022, 8(11), 1199; https://doi.org/10.3390/jof8111199 - 14 Nov 2022

Cited by 5 | Viewed by 1308

Abstract

In this study, a γ-cyclodextrin-cinnamaldehyde inclusion compound (γ-CDCL) was prepared to control green mold caused by Penicillium digitatum (P. digitatum) in citrus. The results showed that the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of γ-CDCL against the mycelial growth of P. digitatum were 2.0 g L⁻¹ and 4.0 g L⁻¹, respectively. Simultaneously, eight × MFC γ-CDCL could effectively reduce the incidence of green mold in citrus fruit without impairment of the fruit qualities, meanwhile, eight × MFC γ-CDCL was comparable to Prochloraz in controlling fruit under natural storage conditions. The structure of γ-CDCL was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FT-IR), and nuclear magnetic resonance (NMR) analyses. Results showed that the successful preparation of γ-CDCL was due to the spatial interaction between H-4,8 of cinnamaldehyde and H-5′ of γ-cyclodextrin. Meanwhile, the cell membrane permeability of P. digitatum was impaired by γ-CDCL through massive accumulation of reactive oxygen species, whereas the cell wall integrity was barely affected. These results indicated that γ-CDCL might inhibit the growth of P. digitatum through a membrane damage mechanism and it is a promising alternative to chemical fungicides in controlling the post-harvest citrus decay. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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18 pages, 2573 KiB

Open AccessArticle

Identification of Bacillus velezensis SBB and Its Antifungal Effects against Verticillium dahliae

by Wei-Yu Wang, Wei-Liang Kong, Yang-Chun-Zi Liao and Li-Hua Zhu

J. Fungi 2022, 8(10), 1021; https://doi.org/10.3390/jof8101021 - 28 Sep 2022

Cited by 10 | Viewed by 2199

Abstract

Traditional control methods have drawbacks in controlling Verticillium wilt diseases caused by Verticillium dahliae Kleb.; therefore, an efficient and environmentally friendly strategy for disease control must be identified and the mechanisms determined. In this study, a soil-isolated strain SBB was identified as Bacillus velezensis based on 16S rRNA, gyrA, and gyrB gene sequences. In vitro, strain SBB had excellent inhibitory effects on V. dahliae, with the highest inhibition rate of 70.94%. Moreover, strain SBB inhibited production of the conidia of V. dahliae and suppressed the production of microsclerotia and melanin. Through gas chromatograph–mass spectrometer analysis, nine compounds were detected from the volatile organic compounds produced by SBB, among which 2-nonanol, 2-heptanone, 6-methyl-2-heptanone, and 2-nonanone could completely inhibit V. dahliae growth. Strain SBB produced cellulase, amylase, protease, and siderophore. During inhibitory action on V. dahliae, strain SBB showed upregulated expression of genes encoding non-volatile inhibitory metabolites, including difficidin, bacilysin, and bacillaene, at 1.923-, 1.848-, and 1.448-fold higher, respectively. Thus, our study proved that strain SBB had an efficient antagonistic effect on V. dahliae, suggesting strain SBB can be used as a potential biological control agent against Verticillium wilt. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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Review

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20 pages, 726 KiB

Open AccessReview

Sources of Antifungal Drugs

by Giel Vanreppelen, Jurgen Wuyts, Patrick Van Dijck and Paul Vandecruys

J. Fungi 2023, 9(2), 171; https://doi.org/10.3390/jof9020171 - 28 Jan 2023

Cited by 15 | Viewed by 6445

Abstract

Due to their eukaryotic heritage, the differences between a fungal pathogen’s molecular makeup and its human host are small. Therefore, the discovery and subsequent development of novel antifungal drugs are extremely challenging. Nevertheless, since the 1940s, researchers have successfully uncovered potent candidates from natural or synthetic sources. Analogs and novel formulations of these drugs enhanced the pharmacological parameters and improved overall drug efficiency. These compounds ultimately became the founding members of novel drug classes and were successfully applied in clinical settings, offering valuable and efficient treatment of mycosis for decades. Currently, only five different antifungal drug classes exist, all characterized by a unique mode of action; these are polyenes, pyrimidine analogs, azoles, allylamines, and echinocandins. The latter, being the latest addition to the antifungal armamentarium, was introduced over two decades ago. As a result of this limited arsenal, antifungal resistance development has exponentially increased and, with it, a growing healthcare crisis. In this review, we discuss the original sources of antifungal compounds, either natural or synthetic. Additionally, we summarize the existing drug classes, potential novel candidates in the clinical pipeline, and emerging non-traditional treatment options. Full article

(This article belongs to the Special Issue Antifungal Discovery of Natural Products)

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