International Journal of Molecular Sciences

Editorial

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4 pages, 200 KiB

Open AccessEditorial

Synthetic and Natural Antifungals—Desirable and Hazardous Effects

by Dejan Stojković, Marija Ivanov and Ana Ćirić

Int. J. Mol. Sci. 2022, 23(17), 9608; https://doi.org/10.3390/ijms23179608 - 25 Aug 2022

Viewed by 1399

Abstract

The increasing incidence of patients struggling with fungal infections, along with high losses in the production of different foods/crops due to fungal diseases presents a significant burden to healthcare, agronomy, and economies worldwide [...] Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

Research

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16 pages, 2499 KiB

Open AccessArticle

Synergistic Antimicrobial Activities of Chitosan Mixtures and Chitosan–Copper Combinations

by Philipp Lemke, Lena Jünemann and Bruno M. Moerschbacher

Int. J. Mol. Sci. 2022, 23(6), 3345; https://doi.org/10.3390/ijms23063345 - 20 Mar 2022

Cited by 10 | Viewed by 3193

Abstract

Several recent studies revealed the significant contribution of intensive agriculture to global climate change and biodiversity decline. However, synthetic pesticides and fertilizers, which are among the main reasons for these negative effects, are required to achieve the high performance of elite crops needed [...] Read more.

Several recent studies revealed the significant contribution of intensive agriculture to global climate change and biodiversity decline. However, synthetic pesticides and fertilizers, which are among the main reasons for these negative effects, are required to achieve the high performance of elite crops needed to feed the growing world population. Modern agro-biologics, such as biopesticides, biostimulants, and biofertilizers are intended to replace or reduce the current agro-chemicals, but the former are often difficult to combine with the latter. Chitosans, produced from the fisheries’ byproduct chitin, are among the most promising agro-biologics, and copper fungicides are among the most widely used plant protectants in organic farming. However, the two active ingredients tend to form precipitates, hindering product development. Here, we show that partial hydrolysis of a chitosan polymer can yield a mixture of smaller polymers and oligomers that act synergistically in their antifungal activity. The low molecular weight (Mw) of this hydrolysate allows its combination with copper acetate, again leading to a synergistic effect. Combined, these synergies allow a 50% reduction in copper concentration, while maintaining the antifungal activity. This is potentially a significant step towards a more sustainable agriculture. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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15 pages, 3058 KiB

Open AccessArticle

Primary Mode of Action of the Novel Sulfonamide Fungicide against Botrytis cinerea and Field Control Effect on Tomato Gray Mold

by Xiaojing Yan, Shuning Chen, Wei Sun, Xiaoxin Zhou, Daibin Yang, Huizhu Yuan and Daoquan Wang

Int. J. Mol. Sci. 2022, 23(3), 1526; https://doi.org/10.3390/ijms23031526 - 28 Jan 2022

Cited by 11 | Viewed by 2678

Abstract

Botrytis cinerea is considered an important plant pathogen and is responsible for significant crop yield losses. With the frequent application of commercial fungicides, B. cinerea has developed resistance to many frequently used fungicides. Therefore, it is necessary to develop new kinds of [...] Read more.

Botrytis cinerea is considered an important plant pathogen and is responsible for significant crop yield losses. With the frequent application of commercial fungicides, B. cinerea has developed resistance to many frequently used fungicides. Therefore, it is necessary to develop new kinds of fungicides with high activity and new modes of action to solve the increasingly serious problem of resistance. During our screening of fungicide candidates, one novel sulfonamide compound, N-(2-trifluoromethyl-4-chlorphenyl)-2-oxocyclohexyl sulfonamide (L13), has been found to exhibit good fungicidal activity against B. cinerea. In this work, the mode of action of L13 against B. cinerea and the field control effect on tomato gray mold was studied. L13 had good control against B. cinerea resistant to carbendazim, diethofencarb, and iprodione commercial fungicides in the pot culture experiments. SEM and TEM observations revealed that L13 could cause obvious morphological and cytological changes to B. cinerea, including excessive branching, irregular ramification or abnormal configuration, and the decomposition of cell wall and vacuole. L13 induced more significant electrolyte leakage from hyphae than procymidone as a positive control. L13 had only a minor effect on the oxygen consumption of intact mycelia, with 2.15% inhibition at 50 μg/mL. In two locations over 2 years, the field control effect of L13 against tomato gray mold reached 83% at a rate of 450 g ai ha⁻¹, better than the commercial fungicide of iprodione. Moreover, toxicological tests demonstrated the low toxicological effect of L13. This research seeks to provide technical support and theoretical guidance for L13 to become a real commercial fungicide. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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27 pages, 2829 KiB

Open AccessArticle

Inhibitory Potential of New Phenolic Hydrazide-Hydrazones with a Decoy Substrate Fragment towards Laccase from a Phytopathogenic Fungus: SAR and Molecular Docking Studies

by Halina Maniak, Michał Talma and Mirosław Giurg

Int. J. Mol. Sci. 2021, 22(22), 12307; https://doi.org/10.3390/ijms222212307 - 14 Nov 2021

Cited by 13 | Viewed by 2860

Abstract

Laccase from pathogenic fungi participates in both the delignification and neutralization of phytoantibiotics. Furthermore, it interferes with the hormone signaling in plants and catalyzes melanization. Infections of these pathogens contribute to loss in forestry, agriculture, and horticulture. As there is still a need [...] Read more.

Laccase from pathogenic fungi participates in both the delignification and neutralization of phytoantibiotics. Furthermore, it interferes with the hormone signaling in plants and catalyzes melanization. Infections of these pathogens contribute to loss in forestry, agriculture, and horticulture. As there is still a need to expand knowledge on efficient defense strategies against phytopathogenic fungi, the present study aimed to reveal more information on the molecular mechanisms of laccase inhibition with natural and natural-like carboxylic acid semi-synthetic derivatives. A set of hydrazide-hydrazones derived from carboxylic acids, generally including electron-rich arene units that serve as a decoy substrate, was synthesized and tested with laccase from Trametes versicolor. The classic synthesis of the title inhibitors proceeded with good to almost quantitative yield. Ninety percent of the tested molecules were active in the range of K_I = 8–233 µM and showed different types of action. Such magnitude of inhibition constants qualified the hydrazide-hydrazones as strong laccase inhibitors. Molecular docking studies supporting the experimental data explained the selected derivatives’ interactions with the enzyme. The results are promising in developing new potential antifungal agents mitigating the damage scale in the plant cultivation, gardening, and horticulture sectors. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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17 pages, 2513 KiB

Open AccessArticle

Steroid-Functionalized Imidazolium Salts with an Extended Spectrum of Antifungal and Antibacterial Activity

by Marta Malinowska, Diana Sawicka, Katarzyna Niemirowicz-Laskowska, Przemysław Wielgat, Halina Car, Tomasz Hauschild and Agnieszka Hryniewicka

Int. J. Mol. Sci. 2021, 22(22), 12180; https://doi.org/10.3390/ijms222212180 - 10 Nov 2021

Cited by 7 | Viewed by 2402

Abstract

It is established that high rates of morbidity and mortality caused by fungal infections are related to the current limited number of antifungal drugs and the toxicity of these agents. Imidazolium salts as azole derivatives can be successfully used in the treatment of [...] Read more.

It is established that high rates of morbidity and mortality caused by fungal infections are related to the current limited number of antifungal drugs and the toxicity of these agents. Imidazolium salts as azole derivatives can be successfully used in the treatment of fungal infections in humans. Steroid-functionalized imidazolium salts were synthesized using a new, more efficient method. As a result, 20 salts were obtained with high yields, 12 of which were synthesized and characterized for the first time. They were derivatives of lithocholic acid and 3-oxo-23,24-dinorchol-4-ene-22-al and were fully characterized by ¹H and ¹³C nuclear magnetic resonance (NMR), infrared spectroscopy (IR), and high resolution mass spectrometry (HRMS). Due to the excellent activity against bacteria and Candida albicans, new research was extended to include tests on five species of pathogenic fungi and molds: Aspergillus niger ATCC 16888, Aspergillus fumigatus ATCC 204305, Trichophyton mentagrophytes ATCC 9533, Cryptococcus neoformans ATCC 14116, and Microsporum canis ATCC 11621. The results showed that the new salts are almost universal antifungal agents and have a broad spectrum of activity against other human pathogens. To initially assess the safety of the synthesized salts, hemocompatibility with host cells and cytotoxicity were also examined. No toxicity was observed at the concentration at which the compounds were active against pathogens. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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14 pages, 11162 KiB

Open AccessArticle

Targeted Delivery of Miconazole Employing LL37 Fragment Mutant Peptide CKR12-Poly (Lactic-Co-Glycolic) Acid Polymeric Micelles

by Takeshi Mori, Miyako Yoshida, Mai Hazekawa, Daisuke Ishibashi, Yoshiro Hatanaka, Rie Kakehashi, Makoto Nakagawa, Toshihiro Nagao, Miki Yoshii, Honami Kojima, Rio Uno and Takahiro Uchida

Int. J. Mol. Sci. 2021, 22(21), 12056; https://doi.org/10.3390/ijms222112056 - 8 Nov 2021

Cited by 4 | Viewed by 2442

Abstract

We previously reported that conjugates of antimicrobial peptide fragment analogues and poly (lactic-co-glycolic) acid (PLGA) enhance antimicrobial activity and that the conjugated micelle structure is an effective tool for antimicrobial drug delivery. In recent years, the delivery of antimicrobial peptides to targets for [...] Read more.

We previously reported that conjugates of antimicrobial peptide fragment analogues and poly (lactic-co-glycolic) acid (PLGA) enhance antimicrobial activity and that the conjugated micelle structure is an effective tool for antimicrobial drug delivery. In recent years, the delivery of antimicrobial peptides to targets for antimicrobial activity has attracted attention. In this study, we targeted Candida albicans, a causative organism of catheter-related bloodstream infections, which is refractory to antimicrobial agents and is currently a problem in medical practice. We evaluated the antifungal activity of CKR12 (a mutant fragment of the human cathelicidin peptide, LL-37)-PLGA-miconazole (MCZ) micelles using nanotechnology with MCZ delivery. The prepared CKR12-PLGA-MCZ micelles were characterised by measuring dynamic light scattering, zeta potential, dilution stability, and drug release. CKR12-PLGA-MCZ micelles showed higher antifungal activity than CKR12-PLGA micelles and MCZ solution. Furthermore, scanning and transmission electron microscopy suggested that CKR12-PLGA-MCZ micelles disrupted both cell wall and cell membrane of C. albicans. Our results revealed a synergistic effect of antifungal activity using a combination of antimicrobial peptide fragment analogues and MCZ, and that MCZ is a promising tool for the delivery to target microorganisms. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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22 pages, 3368 KiB

Open AccessArticle

The Influence of Tea Tree Oil on Antifungal Activity and Pharmaceutical Characteristics of Pluronic^® F-127 Gel Formulations with Ketoconazole

by Magdalena Wróblewska, Emilia Szymańska and Katarzyna Winnicka

Int. J. Mol. Sci. 2021, 22(21), 11326; https://doi.org/10.3390/ijms222111326 - 20 Oct 2021

Cited by 23 | Viewed by 5385

Abstract

Fungal skin infections are currently a major clinical problem due to their increased occurrence and drug resistance. The treatment of fungal skin infections is based on monotherapy or polytherapy using the synergy of the therapeutic substances. Tea tree oil (TTO) may be a [...] Read more.

Fungal skin infections are currently a major clinical problem due to their increased occurrence and drug resistance. The treatment of fungal skin infections is based on monotherapy or polytherapy using the synergy of the therapeutic substances. Tea tree oil (TTO) may be a valuable addition to the traditional antifungal drugs due to its antifungal and anti-inflammatory activity. Ketoconazole (KTZ) is an imidazole antifungal agent commonly used as a treatment for dermatological fungal infections. The use of hydrogels and organogel-based formulations has been increasing for the past few years, due to the easy method of preparation and long-term stability of the product. Therefore, the purpose of this study was to design and characterize different types of Pluronic^® F-127 gel formulations containing KTZ and TTO as local delivery systems that can be applied in cases of skin fungal infections. The influence of TTO addition on the textural, rheological, and bioadhesive properties of the designed formulations was examined. Moreover, the in vitro release of KTZ, its permeation through artificial skin, and antifungal activity by the agar diffusion method were performed. It was found that obtained gel formulations were non-Newtonian systems, showing a shear-thinning behaviour and thixotropic properties with adequate textural features such as hardness, compressibility, and adhesiveness. Furthermore, the designed preparations with TTO were characterized by beneficial bioadhesive properties. The presence of TTO improved the penetration and retention of KTZ through the artificial skin membrane and this effect was particularly visible in hydrogel formulation. The developed gels containing TTO can be considered as favourable formulations in terms of drug release and antifungal activity. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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16 pages, 2257 KiB

Open AccessArticle

Biological Control of Leaf Blight Disease Caused by Pestalotiopsis maculans and Growth Promotion of Quercus acutissima Carruth Container Seedlings Using Bacillus velezensis CE 100

by Sang-Jae Won, Jae-Hyun Moon, Henry B. Ajuna, Su-In Choi, Chaw Ei Htwe Maung, Sangtae Lee and Young Sang Ahn

Int. J. Mol. Sci. 2021, 22(20), 11296; https://doi.org/10.3390/ijms222011296 - 19 Oct 2021

Cited by 20 | Viewed by 3854

Abstract

Leaf blight disease caused by Pestalotiopsismaculans lead to deleterious losses in the quality of forest container seedlings. The use of plant growth-promoting bacteria provides a promising strategy to simultaneously control diseases and enhance forest seedling production. This study investigated the biocontrol of [...] Read more.

Leaf blight disease caused by Pestalotiopsismaculans lead to deleterious losses in the quality of forest container seedlings. The use of plant growth-promoting bacteria provides a promising strategy to simultaneously control diseases and enhance forest seedling production. This study investigated the biocontrol of leaf blight disease and growth promotion potential of Bacillus velezensis CE 100 in Quercus acutissima Carruth seedlings. B. velezensis CE 100 produced cell wall degrading enzymes, such as chitinase, β-l,3-glucanase, and protease, which caused cell wall lysis and hyphae deformation of P. maculans, leading to mycelial growth inhibition by 54.94%. Inoculation of B. velezensis CE 100 suppressed P. maculans infection and increased seedling survival rate by 1.6-fold and 1.3-fold compared to chemical fertilizer and control, respectively. In addition, B. velezensis CE 100 produced indole-3-acetic acid, which improved root development and nutrient uptake compared to chemical fertilizer and control. Especially, inoculation with B. velezensis CE 100 increased the total nitrogen content of Q. acutissima seedlings, improved the chlorophyll index in the leaves, and increased seedling biomass by 1.3-fold and 2.2-fold compared to chemical fertilizer and control, respectively. Thus, B. velezensis CE 100 could be applied in the eco-friendly production of high-quality forest seedlings. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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13 pages, 1679 KiB

Open AccessArticle

Fungicidal Activity and Mechanism of Action of Glabridin from Glycyrrhiza glabra L.

by Anping Li, Zhongmin Zhao, Shaoyong Zhang, Zhijun Zhang and Yanping Shi

Int. J. Mol. Sci. 2021, 22(20), 10966; https://doi.org/10.3390/ijms222010966 - 11 Oct 2021

Cited by 16 | Viewed by 2732

Abstract

Glycyrrhiza glabra (Licorice) belongs to the Fabaceae family and its extracts have exhibited significant fungicidal activity against phytopathogenic fungi, which has mainly been attributed to the presence of phenolic compounds such as flavonoids, isoflavonoids and chalcones. In this study, a series of licorice [...] Read more.

Glycyrrhiza glabra (Licorice) belongs to the Fabaceae family and its extracts have exhibited significant fungicidal activity against phytopathogenic fungi, which has mainly been attributed to the presence of phenolic compounds such as flavonoids, isoflavonoids and chalcones. In this study, a series of licorice flavonoids, isoflavonoids and chalcones were evaluated for their fungicidal activity against phytopathogenic fungi. Among them, glabridin exhibited significant fungicidal activity against ten kinds of phytopathogenic fungi. Notably, glabridin displayed the most active against Sclerotinia sclerotiorum with an EC₅₀ value of 6.78 µg/mL and was 8-fold more potent than azoxystrobin (EC₅₀, 57.39 µg/mL). Moreover, the in vivo bioassay also demonstrated that glabridin could effectively control S. sclerotiorum. The mechanism studies revealed that glabridin could induce reactive oxygen species accumulation, the loss of mitochondrial membrane potential and cell membrane destruction through effecting the expression levels of phosphatidylserine decarboxylase that exerted its fungicidal activity. These findings indicated that glabridin exhibited pronounced fungicidal activities against S. sclerotiorum and could be served as a potential fungicidal candidate. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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15 pages, 4210 KiB

Open AccessArticle

The Antifungal Mechanism of Isoxanthohumol from Humulus lupulus Linn.

by Yin-Fang Yan, Tian-Lin Wu, Sha-Sha Du, Zheng-Rong Wu, Yong-Mei Hu, Zhi-Jun Zhang, Wen-Bin Zhao, Cheng-Jie Yang and Ying-Qian Liu

Int. J. Mol. Sci. 2021, 22(19), 10853; https://doi.org/10.3390/ijms221910853 - 7 Oct 2021

Cited by 21 | Viewed by 2828

Abstract

Humulus lupulus Linn. is a traditional medicinal and edible plant with several biological properties. The aims of this work were: (1) to evaluate the in vitro antifungal activity of H. lupulus ethanolic extract; (2) to study the in vitro and in vivo antifungal [...] Read more.

Humulus lupulus Linn. is a traditional medicinal and edible plant with several biological properties. The aims of this work were: (1) to evaluate the in vitro antifungal activity of H. lupulus ethanolic extract; (2) to study the in vitro and in vivo antifungal activity of isoxanthohumol, an isoprene flavonoid from H. lupulus, against Botrytis cinerea; and (3) to explore the antifungal mechanism of isoxanthohumol on B. cinerea. The present data revealed that the ethanolic extract of H. lupulus exhibited moderate antifungal activity against the five tested phytopathogenic fungi in vitro, and isoxanthohumol showed highly significant antifungal activity against B. cinerea, with an EC₅₀ value of 4.32 µg/mL. Meanwhile, it exhibited moderate to excellent protective and curative efficacies in vivo. The results of morphologic observation, RNA-seq, and physiological indicators revealed that the antifungal mechanism of isoxanthohumol is mainly related to metabolism; it affected the carbohydrate metabolic process, destroyed the tricarboxylic acid (TCA) cycle, and hindered the generation of ATP by inhibiting respiration. Further studies indicated that isoxanthohumol caused membrane lipid peroxidation, thus accelerating the death of B. cinerea. This study demonstrates that isoxanthohumol can be used as a potential botanical fungicide for the management of phytopathogenic fungi. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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18 pages, 28366 KiB

Open AccessArticle

Antifungal Activity of Bacillus velezensis CE 100 against Anthracnose Disease (Colletotrichum gloeosporioides) and Growth Promotion of Walnut (Juglans regia L.) Trees

by Vantha Choub, Henry B. Ajuna, Sang-Jae Won, Jae-Hyun Moon, Su-In Choi, Chaw Ei Htwe Maung, Chul-Woo Kim and Young Sang Ahn

Int. J. Mol. Sci. 2021, 22(19), 10438; https://doi.org/10.3390/ijms221910438 - 28 Sep 2021

Cited by 52 | Viewed by 4487

Abstract

Walnut anthracnose caused by Colletotrichum gloeosporioides is a deleterious disease that severely affects the production of walnut (Juglans regia L.). The aim of this study was to assess the antifungal and growth promotion activities of Bacillus velezensis CE 100 as an alternative [...] Read more.

Walnut anthracnose caused by Colletotrichum gloeosporioides is a deleterious disease that severely affects the production of walnut (Juglans regia L.). The aim of this study was to assess the antifungal and growth promotion activities of Bacillus velezensis CE 100 as an alternative to chemical use in walnut production. The crude enzyme from B. velezensis CE 100 exhibited chitinase, protease, and β-l,3-glucanase activity and degraded the cell wall of C. gloeosporioides, causing the inhibition of spore germination and mycelial growth by 99.3% and 33.6% at 100 µL/mL, respectively. The field application of B. velezensis CE 100 culture broth resulted in a 1.3-fold and 6.9-fold decrease in anthracnose disease severity compared to the conventional and control groups, respectively. Moreover, B. velezensis CE 100 produced indole-3-acetic acid (up to 1.4 µg/mL) and exhibited the potential for ammonium production and phosphate solubilization to enhance the availability of essential nutrients. Thus, field inoculation of B. velezensis CE 100 improved walnut root development, increased nutrient uptake, enhanced chlorophyll content, and consequently improved total biomass by 1.5-fold and 2.0-fold compared to the conventional and control groups, respectively. These results demonstrate that B. velezensis CE 100 is an effective biocontrol agent against anthracnose disease and a potential plant growth-promoting bacteria in walnut tree production. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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16 pages, 56676 KiB

Open AccessArticle

Enhanced Fungicidal Efficacy by Co-Delivery of Azoxystrobin and Diniconazole with Cauliflower-Like Metal–Organic Frameworks NH₂-Al-MIL-101

by Huiping Chen, Yongpan Shan, Lidong Cao, Pengyue Zhao, Chong Cao, Fengmin Li and Qiliang Huang

Int. J. Mol. Sci. 2021, 22(19), 10412; https://doi.org/10.3390/ijms221910412 - 27 Sep 2021

Cited by 22 | Viewed by 3530

Abstract

Long-term use of a single fungicide increases the resistance risk and causes adverse effects on natural ecosystems. Controlled release formulations of dual fungicides with different modes of action can afford a new dimension for addressing the current issues. Based on adjustable aperture and [...] Read more.

Long-term use of a single fungicide increases the resistance risk and causes adverse effects on natural ecosystems. Controlled release formulations of dual fungicides with different modes of action can afford a new dimension for addressing the current issues. Based on adjustable aperture and superhigh surface area, metal–organic frameworks (MOFs) are ideal candidates as pesticide release carriers. This study used Al³⁺ as the metal node and 2-aminoterephthalic acid as the organic chain to prepare aluminum-based metal–organic framework material (NH₂-Al-MIL-101) with “cauliflower-like” structure and high surface area of 2359.0 m²/g. Fungicides of azoxystrobin (AZOX) and diniconazole (Dini) were simultaneously encapsulated into NH₂-Al-MIL-101 with the loading content of 6.71% and 29.72%, respectively. Dual fungicide delivery system of AZOX@Dini@NH₂-Al-MIL-101 demonstrated sustained and pH responsive release profiles. When the maximum cumulative release rate of AZOX and Dini both reached about 90%, the release time was 46 and 136 h, respectively. Furthermore, EC₅₀ values as well as the percentage of inhibition revealed that AZOX@Dini@NH₂-Al-MIL-101 had enhanced germicidal efficacy against rice sheath blight (Rhizoctonia solani), evidenced by the synergistic ratio of 1.83. The present study demonstrates a potential application prospect in sustainable plant protection through co-delivery fungicides with MOFs as a platform. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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14 pages, 2817 KiB

Open AccessArticle

Camphor and Eucalyptol—Anticandidal Spectrum, Antivirulence Effect, Efflux Pumps Interference and Cytotoxicity

by Marija Ivanov, Abhilash Kannan, Dejan S. Stojković, Jasmina Glamočlija, Ricardo C. Calhelha, Isabel C. F. R. Ferreira, Dominique Sanglard and Marina Soković

Int. J. Mol. Sci. 2021, 22(2), 483; https://doi.org/10.3390/ijms22020483 - 6 Jan 2021

Cited by 48 | Viewed by 4039

Abstract

Candidaalbicans represents one of the most common fungal pathogens. Due to its increasing incidence and the poor efficacy of available antifungals, finding novel antifungal molecules is of great importance. Camphor and eucalyptol are bioactive terpenoid plant constituents and their antifungal properties have [...] Read more.

Candidaalbicans represents one of the most common fungal pathogens. Due to its increasing incidence and the poor efficacy of available antifungals, finding novel antifungal molecules is of great importance. Camphor and eucalyptol are bioactive terpenoid plant constituents and their antifungal properties have been explored previously. In this study, we examined their ability to inhibit the growth of different Candida species in suspension and biofilm, to block hyphal transition along with their impact on genes encoding for efflux pumps (CDR1 and CDR2), ergosterol biosynthesis (ERG11), and cytotoxicity to primary liver cells. Camphor showed excellent antifungal activity with a minimal inhibitory concentration of 0.125–0.35 mg/mL while eucalyptol was active in the range of 2–23 mg/mL. The results showed camphor’s potential to reduce fungal virulence traits, that is, biofilm establishment and hyphae formation. On the other hand, camphor and eucalyptol treatments upregulated CDR1;CDR2 was positively regulated after eucalyptol application while camphor downregulated it. Neither had an impact on ERG11 expression. The beneficial antifungal activities of camphor were achieved with an amount that was non-toxic to porcine liver cells, making it a promising antifungal compound for future development. The antifungal concentration of eucalyptol caused cytotoxic effects and increased expression of efflux pump genes, which suggests that it is an unsuitable antifungal candidate. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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Review

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26 pages, 1774 KiB

Open AccessReview

Emerging Antifungal Targets and Strategies

by Marija Ivanov, Ana Ćirić and Dejan Stojković

Int. J. Mol. Sci. 2022, 23(5), 2756; https://doi.org/10.3390/ijms23052756 - 2 Mar 2022

Cited by 67 | Viewed by 9862

Abstract

Despite abundant research in the field of antifungal drug discovery, fungal infections remain a significant healthcare burden. There is an emerging need for the development of novel antifungals since those currently available are limited and do not completely provide safe and secure protection. [...] Read more.

Despite abundant research in the field of antifungal drug discovery, fungal infections remain a significant healthcare burden. There is an emerging need for the development of novel antifungals since those currently available are limited and do not completely provide safe and secure protection. Since the current knowledge regarding the physiology of fungal cells and the infection mechanisms is greater than ever, we have the opportunity to use this for the development of novel generations of antifungals. In this review, we selected and summarized recent studies describing agents employing different antifungal mechanisms. These mechanisms include interference with fungal resistance, including impact on the efflux pumps and heat shock protein 90. Additionally, interference with virulence factors, such as biofilms and hyphae; the impact on fungal enzymes, metabolism, mitochondria, and cell wall; and antifungal vaccines are explored. The agents investigated belong to different classes of natural or synthetic molecules with significant attention given also to plant extracts. The efficacy of these antifungals has been studied mainly in vitro with some in vivo, and clinical studies are needed. Nevertheless, there is a large quantity of products employing novel antifungal mechanisms that can be further explored for the development of new generation of antifungals. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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12 pages, 261 KiB

Open AccessReview

SDHI Fungicide Toxicity and Associated Adverse Outcome Pathways: What Can Zebrafish Tell Us?

by Constantin Yanicostas and Nadia Soussi-Yanicostas

Int. J. Mol. Sci. 2021, 22(22), 12362; https://doi.org/10.3390/ijms222212362 - 16 Nov 2021

Cited by 33 | Viewed by 4688

Abstract

Succinate dehydrogenase inhibitor (SDHI) fungicides are increasingly used in agriculture to combat molds and fungi, two major threats to both food supply and public health. However, the essential requirement for the succinate dehydrogenase (SDH) complex—the molecular target of SDHIs—in energy metabolism for almost [...] Read more.

Succinate dehydrogenase inhibitor (SDHI) fungicides are increasingly used in agriculture to combat molds and fungi, two major threats to both food supply and public health. However, the essential requirement for the succinate dehydrogenase (SDH) complex—the molecular target of SDHIs—in energy metabolism for almost all extant eukaryotes and the lack of species specificity of these fungicides raise concerns about their toxicity toward off-target organisms and, more generally, toward the environment. Herein we review the current knowledge on the toxicity toward zebrafish (Brachydanio rerio) of nine commonly used SDHI fungicides: bixafen, boscalid, fluxapyroxad, flutolanil, isoflucypram, isopyrazam, penthiopyrad, sedaxane, and thifluzamide. The results indicate that these SDHIs cause multiple adverse effects in embryos, larvae/juveniles, and/or adults, sometimes at developmentally relevant concentrations. Adverse effects include developmental toxicity, cardiovascular abnormalities, liver and kidney damage, oxidative stress, energy deficits, changes in metabolism, microcephaly, axon growth defects, apoptosis, and transcriptome changes, suggesting that glycometabolism deficit, oxidative stress, and apoptosis are critical in the toxicity of most of these SDHIs. However, other adverse outcome pathways, possibly involving unsuspected molecular targets, are also suggested. Lastly, we note that because of their recent arrival on the market, the number of studies addressing the toxicity of these compounds is still scant, emphasizing the need to further investigate the toxicity of all SDHIs currently used and to identify their adverse effects and associated modes of action, both alone and in combination with other pesticides. Full article

(This article belongs to the Special Issue Synthetic and Natural Antifungals—Desirable and Hazardous Effects)

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