Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

In the last few years, increasing importance is attached to problems caused by fungal pathogens. Current methods of preventing fungal infections remain unsatisfactory. There are several antifungal compounds which are highly effective in some cases, however, they have limitations in usage: Nephrotoxicity and other adverse effects. In addition, the frequent use of available fungistatic drugs promotes drug resistance. Therefore, there is an urgent need for the development of a novel antifungal drug with a different mechanism of action, blocking of the fungal DNA topoisomerases activity appear to be a promising idea. According to previous studies on the m-AMSA moderate inhibitory effect on fungal topoisomerase II, we have decided to study Capridine β (also acridine derivative) antifungal activity, as well as its inhibitory potential on yeast topoisomerase II (yTOPOII). Results indicated that Capridine β antifungal activity depends on the kind of strains analyzed (MICs range 0.5–64 μg mL−1) and is related to its biotransformation in the cells. An investigation of metabolite formation, identified as Capridine β reduction product (IE1) by the fungus Candida albicans was performed. IE1 exhibited no activity against fungal cells due to an inability to enter the cells. Although no antifungal activity was observed, in contrast to Capridine β, biotransformation metabolite totally inhibited the yTOPOII-mediated relaxation at concentrations lower than detected for m-AMSA. The closely related Capridine β only slightly diminished the catalytic activity of yTOPOII.

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Antifungal Efficacy of Marine Macroalgae against Fungal Isolates from Bronchial Asthmatic Cases

Molecules ◽

10.3390/molecules23113032 ◽

2018 ◽

Vol 23 (11) ◽

pp. 3032 ◽

Cited By ~ 14

Author(s):

Suresh Mickymaray ◽

Wael Alturaiki

Keyword(s):

Antifungal Activity ◽

Fungal Pathogens ◽

Fungal Infections ◽

Algal Species ◽

Marine Macroalgae ◽

Minimum Fungicidal Concentration ◽

Asthmatic Patients ◽

The Cost ◽

Algal Extracts ◽

Airway Colonization

Fungal sensitization is very common in bronchial asthmatic cases, and the connection with airway colonization by fungi remains uncertain. Antifungal therapy failure is a significant fraction of the cost and morbidity and mortality in the majority of the asthmatic cases. Hence, the present study aimed to investigate the antifungal activity of five marine macroalgae—Acanthaophora specifera, Cladophoropsis sp., Laurencia paniculata, Tydemania sp., and Ulva prolifera—which were tested on selected fungal pathogens isolated from 15 sputum of 45 bronchial asthmatic patients. The highest antifungal activity was observed in ethanol fractions of L. paniculata followed by U. prolifera, Cladophoropsis sp., A. specifera, and Tydemania sp. The minimum fungicidal concentration and minimum inhibitory concentration values of the ethanolic fractions of algal species were found to be 125–1000 µg/mL and 125–500 µg/mL, respectively. The algal extracts contained terpene alcohol, diterpene, steroids, sesquiterpene, and sesquiterpene alcohol, as determined by GC–MS/MS analyses. The present study shows that the marine macroalgae containing bioactive compounds had excellent inhibitory activity against a variety of fungal pathogens, which may be useful for combating fungal infections and recovering from chronic asthmatic states.

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Control of Panama disease of banana by intercropping with Chinese chive (Allium tuberosum Rottler): cultivar differences

BMC Plant Biology ◽

10.1186/s12870-020-02640-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Zhenfang Li ◽

Tong Wang ◽

Chenling He ◽

Kelin Cheng ◽

Rensen Zeng ◽

...

Keyword(s):

Antifungal Activity ◽

Field Experiments ◽

Disease Incidence ◽

Inhibitory Effect ◽

Cultivar Differences ◽

Antifungal Compounds ◽

Panama Disease ◽

Allium Tuberosum ◽

Leaf Volatiles ◽

Chinese Chive

Abstract Panama disease (Fusarium wilt disease) caused by Fusarium oxysporum f. sp. cubense race 4 (FOC) severely threatens banana (Musa spp.) production worldwide. Intercropping of banana with Allium plants has shown a potential to reduce Panama disease. In this study, six cultivars of Chinese chive (Allium tuberosum Rottler) were selected to compare their differences in antifungal activity and active compounds. Three cultivars Duokang Fujiu 11, Fujiuhuang 2, and Duokang Sijiqing with higher levels of antifungal compounds were further used for intercropping with banana in the pots and field to compare their effects on growth and disease incidence of banana. The six cultivars showed significant differences in antifungal activity against FOC mycelia growth in both leaf volatiles and aqueous leachates. The aqueous leachates displayed stronger antifungal activity than the volatiles. FJH cultivar showed the best inhibitory effect among all six cultivars. Contents of three main antifungal compounds dipropyl trisulfide (DPT), dimethyl trisulfide (DMT), and 2-methyl-2-pentenal (MP) in volatiles and aqueous leachates varied considerably among cultivars. Pot and field experiments showed that intercropping with three selected Chinese chive cultivars significantly improved banana vegetative growth, increased photosynthetic characteristics and yield but decreased disease incidence of Panama disease. Our results indicate that intercropping with Chinese chive shows potential to reduce banana Panama disease and selection of appropriate cultivars is vital for effective disease control.

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Control of Panama disease of banana by intercropping with Chinese chive (Allium tuberosum Rottler): cultivar differences

10.21203/rs.3.rs-25892/v4 ◽

2020 ◽

Author(s):

Zhen-Fang Li ◽

Tong Wang ◽

Chenling He ◽

Kelin Cheng ◽

Rensen Zeng ◽

...

Keyword(s):

Antifungal Activity ◽

Field Experiments ◽

Disease Incidence ◽

Inhibitory Effect ◽

Cultivar Differences ◽

Antifungal Compounds ◽

Panama Disease ◽

Allium Tuberosum ◽

Leaf Volatiles ◽

Chinese Chive

Abstract Panama disease (Fusarium wilt disease) caused by Fusarium oxysporum f. sp. cubense race 4 (FOC) severely threatens banana (Musa spp.) production worldwide. Intercropping of banana with Allium plants has shown a potential to reduce Panama disease. In this study, six cultivars of Chinese chive (Allium tuberosum Rottler) were selected to compare their differences in antifungal activity and active compounds. Three cultivars Duokang Fujiu 11, Fujiuhuang 2, and Duokang Sijiqing with higher levels of antifungal compounds were further used for intercropping with banana in the pots and field to compare their effects on growth and disease incidence of banana. The six cultivars showed significant differences in antifungal activity against FOC mycelia growth in both leaf volatiles and aqueous leachates. The aqueous leachates displayed stronger antifungal activity than the volatiles. FJH cultivar showed the best inhibitory effect among all six cultivars. Contents of three main antifungal compounds dipropyl trisulfide (DPT), dimethyl trisulfide (DMT), and 2-methyl-2-pentenal (MP) in volatiles and aqueous leachates varied considerably among cultivars. Pot and field experiments showed that intercropping with three selected Chinese chive cultivars significantly improved banana vegetative growth, increased photosynthetic characteristics and yield but decreased disease incidence of Panama disease.Our results indicate that intercropping with Chinese chive shows potential to reduce banana Panama disease and selection of appropriate cultivars is vital for effective disease control.

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Toxoflavin Produced byBurkholderia gladiolifromLycoris aureaIs a New Broad-Spectrum Fungicide

Applied and Environmental Microbiology ◽

10.1128/aem.00106-19 ◽

2019 ◽

Vol 85 (9) ◽

Cited By ~ 7

Author(s):

Xiaodan Li ◽

Yikui Li ◽

Ren Wang ◽

Qizhi Wang ◽

Ling Lu

Keyword(s):

Antifungal Activity ◽

Broad Spectrum ◽

Fungal Pathogens ◽

Antifungal Agents ◽

Fungal Infections ◽

Endophytic Bacterium ◽

Content Type ◽

Burkholderia Gladioli ◽

Lycoris Aurea ◽

Resistant Mutants

ABSTRACTFungal infections not only cause extensive agricultural damage but also result in serious diseases in the immunodeficient populations of human beings. Moreover, the increasing emergence of drug resistance has led to a decrease in the efficacy of current antifungals. Thus, screening of new antifungal agents is imperative in the fight against antifungal drug resistance. In this study, we show that an endophytic bacterium,Burkholderia gladioliHDXY-02, isolated from the medicinal plantLycoris aurea, showed broad-spectrum antifungal activity against plant and human fungal pathogens. An antifungal ability assay indicated that the bioactive component was produced from strain HDXY-02 having an extracellular secreted component with a molecular weight lower than 1,000 Da. In addition, we found that this new antifungal could be produced effectively by liquid fermentation of HDXY-02. Furthermore, the purified component contributing to the antifungal activity was identified to be toxoflavin, a yellow compound possessing a pyrimido[5,4-e][1,2,4]triazine ring.In vitrobioactivity studies demonstrated that purified toxoflavin fromB. gladioliHDXY-02 cultures had a significant antifungal activity against the human fungal pathogenAspergillus fumigatus, resulting in abolished germination of conidia. More importantly, the growth inhibition by toxoflavin was observed in both wild-type and drug-resistant mutants (cyp51Aand non-cyp51A) ofA. fumigatus. Finally, an optimized protocol for the large-scale production of toxoflavin (1,533 mg/liter) has been developed. Taken together, our findings provide a promising biosynthetic resource for producing a new antifungal reagent, toxoflavin, from isolates of the endophytic bacteriumB. gladioli.IMPORTANCEHuman fungal infections are a growing problem associated with increased morbidity and mortality. Moreover, a growing number of antifungal-resistant fungal isolates have been reported over the past decade. Thus, the need for novel antifungal agents is imperative. In this study, we show that an endophytic bacterium,Burkholderia gladioli, isolated from the medicinal plantLycoris aurea, is able to abundantly secrete a compound, toxoflavin, which has a strong fungicidal activity not only against plant fungal pathogens but also against human fungal pathogensAspergillus fumigatusandCandida albicans,Cryptococcus neoformans, and the model filamentous fungusAspergillus nidulans. More importantly, toxoflavin also displays an efficacious inhibitory effect against azole antifungal-resistant mutants ofA. fumigatus. Consequently, our findings provide a promising approach to abundantly produce toxoflavin, which has novel broad-spectrum antifungal activity, especially against those currently problematic drug-resistant isolates.

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Anticapsular and Antifungal Activity of α-Cyperone

Antibiotics ◽

10.3390/antibiotics10010051 ◽

2021 ◽

Vol 10 (1) ◽

pp. 51

Author(s):

Connor Horn ◽

Govindsamy Vediyappan

Keyword(s):

Antifungal Activity ◽

Fungal Pathogens ◽

Fungal Infections ◽

Antifungal Drugs ◽

Cyperus Rotundus ◽

Drug Resistant ◽

Fungal Virulence ◽

Medical Needs ◽

Number Of Patients ◽

Immunosuppressed Patients

Fungal infections affect 300 million people and cause 1.5 million deaths globally per year. With the number of immunosuppressed patients increasing steadily, there is an increasing number of patients infected with opportunistic fungal infections such as infections caused by the species of Candida and Cryptococcus. In fact, the drug-resistant Can. krusei and the emerging pan-antifungal resistant Can. auris pose a serious threat to human health as the existing limited antifungals are futile. To further complicate therapy, fungi produce capsules and spores that are resistant to most antifungal drugs/host defenses. Novel antifungal drugs are urgently needed to fill unmet medical needs. From screening a collection of medicinal plant sources for antifungal activity, we have identified an active fraction from the rhizome of Cyperus rotundus, the nut grass plant. The fraction contained α-Cyperone, an essential oil that showed fungicidal activity against different species of Candida. Interestingly, the minimal inhibitory concentration of α-Cyperone was reduced 8-fold when combined with a clinical antifungal drug, fluconazole, indicating its antifungal synergistic potential and could be useful for combination therapy. Furthermore, α-Cyperone affected the synthesis of the capsule in Cryp. neoformans, a causative agent of fungal meningitis in humans. Further work on mechanistic understanding of α-Cyperone against fungal virulence could help develop a novel antifungal agent for drug-resistant fungal pathogens.

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Antifungal Activity and DNA Topoisomerase Inhibition of Hydrolisable Tannins from Punica granatum L.

International Journal of Molecular Sciences ◽

10.3390/ijms22084175 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4175

Author(s):

Virginia Brighenti ◽

Ramona Iseppi ◽

Luca Pinzi ◽

Annamaria Mincuzzi ◽

Antonio Ippolito ◽

...

Keyword(s):

Phenolic Compounds ◽

Antifungal Activity ◽

Active Compound ◽

Fungal Pathogens ◽

Fungal Infections ◽

Punica Granatum ◽

Human Pathogens ◽

First Time ◽

Punica Granatum L

Punica granatum L. (pomegranate) fruit is known to be an important source of bioactive phenolic compounds belonging to hydrolysable tannins. Pomegranate extracts have shown antifungal activity, but the compounds responsible for this activity and their mechanism/s of action have not been completely elucidated up to now. The aim of the present study was the investigation of the inhibition ability of a selection of pomegranate phenolic compounds (i.e., punicalagin, punicalin, ellagic acid, gallic acid) on both plant and human fungal pathogens. In addition, the biological target of punicalagin was identified here for the first time. The antifungal activity of pomegranate phenolics was evaluated by means of Agar Disk Diffusion Assay and minimum inhibitory concentration (MIC) evaluation. A chemoinformatic analysis predicted for the first time topoisomerases I and II as potential biological targets of punicalagin, and this prediction was confirmed by in vitro inhibition assays. Concerning phytopathogens, all the tested compounds were effective, often similarly to the fungicide imazalil at the label dose. Particularly, punicalagin showed the lowest MIC for Alternaria alternata and Botrytis cinerea, whereas punicalin was the most active compound in terms of growth control extent. As for human pathogens, punicalagin was the most active compound among the tested ones against Candida albicans reference strains, as well as against the clinically isolates. UHPLC coupled with HRMS indicated that C. albicans, similarly to the phytopathogen Coniella granati, is able to hydrolyze both punicalagin and punicalin as a response to the fungal attack. Punicalagin showed a strong inhibitory activity, with IC50 values of 9.0 and 4.6 µM against C. albicans topoisomerases I and II, respectively. Altogether, the results provide evidence that punicalagin is a valuable candidate to be further exploited as an antifungal agent in particular against human fungal infections.

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Isolation, Characterization and Mode of Action of a Plant-Derived Antifungal Peptide, Cc-AFP1 Against Aspergillus Fumigatus

10.21203/rs.3.rs-571433/v1 ◽

2021 ◽

Author(s):

Sima Sadat Seyedjavadi ◽

Soghra Khani ◽

Mehdi Goudarzi ◽

Hadi Zare-Zardini ◽

Masoomeh Shams-Ghahfarokhi ◽

...

Keyword(s):

Antifungal Activity ◽

Structure Prediction ◽

Fungal Pathogens ◽

Tertiary Structure ◽

Fungal Infections ◽

Cell Membrane Permeability ◽

Random Coil ◽

Iodide Uptake ◽

Fungal Cell ◽

Human Red Blood Cells

Abstract Among novel molecules with therapeutic efficacy, antifungal peptides (AFPs) have recently been attracted due to their unique ability to evade fungal pathogens. In this study, a novel AFP, Cc-AFP1 (MW ~ 3.759 kDa) isolated from Carum carvi L. was purified by precipitation and chromatography techniques. Sequence analysis by Edman degradation revealed a fragment of 36 amino acid residues as RVCFRPVATYLGVCGVSGACRDHCVKLGSCVYKGPG. The tertiary structure prediction using the I-TASSER showed α-helix and random coil structure. Cc-AFP1 had a net charge of +4 and hydrophobicity ratio of 44%. The antifungal activity of Cc-AFP1 was confirmed against Aspergillus species with MIC values in the range of 8-16 µg/mL. Cc-AFP1 had less than 5% hemolytic activity at 8-16 µg/mL on human red blood cells, while it was nontoxic for HEK293 cell lines. Stability analysis showed that Cc-AFP1 activity was maintained at different temperatures (20 to 80ºC) and pH (8 to 10). The results of a propidium iodide uptake and transmission electron microscopy showed that the antifungal activity of Cc-AFP1 could be attributed to altering the fungal cell membrane permeability. Taken together, these results indicate that Cc-AFP1 may be an attractive molecule to develop as a novel antifungal agent combating fungal infections cause by Aspergillus species.

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Antifungal Activity of N-(4-Halobenzyl)amides against Candida spp. and Molecular Modeling Studies

International Journal of Molecular Sciences ◽

10.3390/ijms23010419 ◽

2021 ◽

Vol 23 (1) ◽

pp. 419

Author(s):

Yunierkis Perez-Castillo ◽

Ricardo Carneiro Montes ◽

Cecília Rocha da Silva ◽

João Batista de Andrade Neto ◽

Celidarque da Silva Dias ◽

...

Keyword(s):

Antifungal Activity ◽

Benzoic Acid ◽

Mechanism Of Action ◽

Fungal Infections ◽

Redox Balance ◽

Inhibitory Effect ◽

Candida Spp ◽

Cellular Processes ◽

Antifungal Action ◽

Dynamics Simulations

Fungal infections remain a high-incidence worldwide health problem that is aggravated by limited therapeutic options and the emergence of drug-resistant strains. Cinnamic and benzoic acid amides have previously shown bioactivity against different species belonging to the Candida genus. Here, 20 cinnamic and benzoic acid amides were synthesized and tested for inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019. Five compounds inhibited the Candida strains tested, with compound 16 (MIC = 7.8 µg/mL) producing stronger antifungal activity than fluconazole (MIC = 16 µg/mL) against C. krusei ATCC 14243. It was also tested against eight Candida strains, including five clinical strains resistant to fluconazole, and showed an inhibitory effect against all strains tested (MIC = 85.3–341.3 µg/mL). The MIC value against C. krusei ATCC 6258 was 85.3 mcg/mL, while against C. krusei ATCC 14243, it was 10.9 times smaller. This strain had greater sensitivity to the antifungal action of compound 16. The inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019 was also achieved by compounds 2, 9, 12, 14 and 15. Computational experiments combining target fishing, molecular docking and molecular dynamics simulations were performed to study the potential mechanism of action of compound 16 against C. krusei. From these, a multi-target mechanism of action is proposed for this compound that involves proteins related to critical cellular processes such as the redox balance, kinases-mediated signaling, protein folding and cell wall synthesis. The modeling results might guide future experiments focusing on the wet-lab investigation of the mechanism of action of this series of compounds, as well as on the optimization of their inhibitory potency.

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Hexadecylphosphocholine (Miltefosine) Has Broad-Spectrum Fungicidal Activity and Is Efficacious in a Mouse Model of Cryptococcosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.2.414-421.2006 ◽

2006 ◽

Vol 50 (2) ◽

pp. 414-421 ◽

Cited By ~ 95

Author(s):

Fred Widmer ◽

Lesley C. Wright ◽

Daniel Obando ◽

Rosemary Handke ◽

Ranjini Ganendren ◽

...

Keyword(s):

Antifungal Activity ◽

Mouse Model ◽

Broad Spectrum ◽

Fungal Pathogens ◽

Inhibitory Effect ◽

Fungal Virulence ◽

Antifungal Effect ◽

Pancreatic Phospholipase ◽

Scedosporium Prolificans

ABSTRACT The alkyl phosphocholine drug miltefosine is structurally similar to natural substrates of the fungal virulence determinant phospholipase B1 (PLB1), which is a potential drug target. We determined the MICs of miltefosine against key fungal pathogens, correlated antifungal activity with inhibition of the PLB1 activities (PLB, lysophospholipase [LPL], and lysophospholipase-transacylase [LPTA]), and investigated its efficacy in a mouse model of disseminated cryptococcosis. Miltefosine inhibited secreted cryptococcal LPTA activity by 35% at the subhemolytic concentration of 25 μM (10.2 μg/ml) and was inactive against mammalian pancreatic phospholipase A2 (PLA2). At 250 μM, cytosolic PLB, LPL, and LPTA activities were inhibited by 25%, 51%, and 77%, respectively. The MICs at which 90% of isolates were inhibited (MIC90s) against Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Cryptococcus gattii, Aspergillus fumigatus, Fusarium solani, Scedosporium prolificans, and Scedosporium apiospermum were 2 to 4 μg/ml. The MICs of miltefosine against Candida tropicalis (n = 8) were 2 to 4 μg/ml, those against Aspergillus terreus and Candida parapsilosis were 8 μg/ml (MIC90), and those against Aspergillus flavus (n = 8) were 2 to 16 μg/ml. Miltefosine was fungicidal for C. neoformans, with rates of killing of 2 log units within 4 h at 7.0 μM (2.8 μg/ml). Miltefosine given orally to mice on days 1 to 5 after intravenous infection with C. neoformans delayed the development of illness and mortality and significantly reduced the brain cryptococcal burden. We conclude that miltefosine has broad-spectrum antifungal activity and is active in vivo in a mouse model of disseminated cryptococcosis. The relatively small inhibitory effect on PLB1 enzyme activities at concentrations exceeding the MIC by 2 to 20 times suggests that PLB1 inhibition is not the only mechanism of the antifungal effect.

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Antifungal activity in thrips soldiers suggests a dual role for this caste

Biology Letters ◽

10.1098/rsbl.2012.0184 ◽

2012 ◽

Vol 8 (4) ◽

pp. 526-529 ◽

Cited By ~ 14

Author(s):

Christine Turnbull ◽

Holly Caravan ◽

Thomas Chapman ◽

David Nipperess ◽

Siobhan Dennison ◽

...

Keyword(s):

Antifungal Activity ◽

Fungal Pathogen ◽

Fungal Pathogens ◽

Social Insect ◽

Antifungal Compounds ◽

Response To Selection ◽

Male And Female ◽

The Social ◽

Selective Agents ◽

Micro Organisms

The social insect soldier is perhaps the most widely known caste, because it often exhibits spectacular weapons, such as highly enlarged jaws or reinforced appendages, which are used to defend the colony against enemies ranging in size from wasps to anteaters. We examined the function of the enlarged forelimbs of soldiers (both male and female) of the eusocial, gall-inhabiting insect Kladothrips intermedius , and discovered that they have little impact on their ability to repel the specialized invading thrips Koptothrips species. While the efficacy of the enlarged forelimb appears equivocal, we show that soldiers secrete strong antifungal compounds capable of controlling the specialized insect fungal pathogen, Cordyceps bassiana . Our data suggest that these thrips soldiers have evolved in response to selection by both macro- and micro-organisms. While it is unknown whether specialized fungal pathogens have been major selective agents in the evolution of the soldier caste in general, they were probably present when sociality first evolved and may have been the primordial enemies of social insects.

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