scholarly journals Antifungal Activities and Cytotoxicity Studies of Six New Azasordarins

2001 ◽  
Vol 45 (11) ◽  
pp. 3132-3139 ◽  
Author(s):  
Esperanza Herreros ◽  
Maria Jesus Almela ◽  
Sonia Lozano ◽  
Federico Gomez De Las Heras ◽  
Domingo Gargallo-Viola
Keyword(s):  
Cryptococcus Neoformans ◽  
Cell Lines ◽  
Fungal Pathogens ◽  
Pneumocystis Carinii ◽  
Pathogenic Fungi ◽  
Significant Activity ◽  
Absidia Corymbifera ◽  
Mammalian Cell Lines ◽  
Cytotoxicity Studies

ABSTRACT GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 are members of a new family of sordarin derivatives called azasordarins. The in vitro activities of these compounds were evaluated against clinical isolates of yeasts, including Candida albicans, Candida non-albicans, and Cryptococcus neoformans strains. Activities againstPneumocystis carinii, Aspergillus spp., less common molds, and dermatophytes were also investigated. Azasordarin derivatives displayed significant activities against the most clinically important Candida species, with the exception of C. krusei. Against C. albicans, including fluconazole-resistant strains, MICs at which 90% of the isolates tested are inhibited (MIC90s) were 0.002 μg/ml with GW 479821, 0.015 μg/ml with GW 515716 and GW 587270, and 0.06 μg/ml with GW 471552, GW 471558, and GW 570009. The MIC90s of GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 were 0.12, 0.12, 0.03, 0.06, 0.12, and 0.06 μg/ml, respectively, against C. tropicalis and 4, 0.25, 0.06, 0.25, 0.5, and 0.5 μg/ml, respectively, against C. glabrata. In addition, some azasordarin derivatives (GW 479821, GW 515716, GW 570009, and GW 58720) were active against C. parapsilosis, with MIC90s of 2, 4, 4, and 1 μg/ml, respectively. The compounds were extremely potent againstP. carinii, showing 50% inhibitory concentrations of ≤0.001 μg/ml. However Cryptococcus neoformans was resistant to all compounds tested (MIC > 16 μg/ml). These azasordarin derivatives also showed significant activity against emerging fungal pathogens, which affect immunocompromised patients, such as Rhizopus arrhizus, Blastoschizomyces capitatus, and Geotrichum clavatum. Against these organisms, the MICs of GW 587270 ranged from 0.12 to 1 μg/ml, those of GW 479821 and GW 515716 ranged from 0.12 to 2 μg/ml, and those of GW 570009 ranged from 0.12 to 4 μg/ml. AgainstFusarium oxysporum, Scedosporium apiospermum, Absidia corymbifera,Cunninghamella bertholletiae, and dermatophytes, GW 587270 was the most active compound, with MICs ranging from 4 to 16 μg/ml. Against Aspergillus spp., the MICs of the compounds tested were higher than 16 μg/ml. The in vitro selectivity of azasordarins was investigated by cytotoxicity studies performed with five cell lines and primary hepatocytes. Concentrations of compound required to achieve 50% inhibition of the parameter considered (Tox50s) of GW 570009, GW 587270, GW 479281, and GW 515716 in the cell lines ranged from 60 to 96, 49 to 62, 24 to 36, and 16 to 38 μg/ml, respectively. The cytotoxicity values of GW 471552 and GW 471558 were >100 μg/ml for all cell lines tested. Tox50s on hepatocytes were in the following order: GW 471558 > GW 471552 > GW 570009 > GW 587270 > GW 515716 > GW 479821, with values ranging from higher than 100 μg/ml to 23 μg/ml. The cytotoxicity results obtained with fully metabolizing rat hepatocytes were in total agreement with those obtained with cell lines. In summary, the in vitro activities against important pathogenic fungi and the selectivity demonstrated in mammalian cell lines justify additional studies to determine the clinical usefulness of azasordarins.

Sordarins: In Vitro Activities of New Antifungal Derivatives against Pathogenic Yeasts, Pneumocystis carinii, and Filamentous Fungi

1998 ◽  
Vol 42 (11) ◽  
pp. 2863-2869 ◽  
Author(s):  
E. Herreros ◽  
C. M. Martinez ◽  
M. J. Almela ◽  
M. S. Marriott ◽  
F. Gomez De Las Heras ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Filamentous Fungi ◽  
Fungal Pathogens ◽  
Pneumocystis Carinii ◽  
Pathogenic Fungi ◽  
Pseudallescheria Boydii ◽  
Absidia Corymbifera ◽  
Wide Range ◽  
Blastoschizomyces Capitatus

ABSTRACT GM 193663, GM 211676, GM 222712, and GM 237354 are new semisynthetic derivatives of the sordarin class. The in vitro antifungal activities of GM 193663, GM 211676, GM 222712, and GM 237354 against 111 clinical yeast isolates of Candida albicans,Candida kefyr, Candida glabrata, Candida parapsilosis, Candida krusei, and Cryptococcus neoformans were compared. The in vitro activities of some of these compounds against Pneumocystis carinii, 20 isolates each of Aspergillus fumigatus and Aspergillus flavus, and 30 isolates of emerging less-common mold pathogens and dermatophytes were also compared. The MICs of GM 193663, GM 211676, GM 222712, and GM 237354 at which 90% of the isolates were inhibited (MIC90s) were 0.03, 0.03, 0.004, and 0.015 μg/ml, respectively, for C. albicans, including strains with decreased susceptibility to fluconazole; 0.5, 0.5, 0.06, and 0.12 μg/ml, respectively, for C. tropicalis; and 0.004, 0.015, 0.008, and 0.03 μg/ml, respectively, forC. kefyr. GM 222712 and GM 237354 were the most active compounds against C. glabrata, C. parapsilosis, and Cryptococcus neoformans. AgainstC. glabrata and C. parapsilosis, the MIC90s of GM 222712 and GM 237354 were 0.5 and 4 μg/ml and 1 and 16 μg/ml, respectively. The MIC90s of GM 222712 and GM 237354 againstCryptococcus neoformans were 0.5 and 0.25 μg/ml, respectively. GM 193663, GM 211676, GM 222712, and GM 237354 were extremely active against P. carinii. The efficacies of sordarin derivatives against this organism were determined by measuring the inhibition of the uptake and incorporation of radiolabelled methionine into newly synthesized proteins. All compounds tested showed 50% inhibitory concentrations of <0.008 μg/ml. Against A. flavus and A. fumigatus, the MIC90s of GM 222712 and GM 237354 were 1 and 32 μg/ml and 32 and >64 μg/ml, respectively. In addition, GM 237354 was tested against the most important emerging fungal pathogens which affect immunocompromised patients. Cladosporium carrioni, Pseudallescheria boydii, and the yeast-like fungi Blastoschizomyces capitatus and Geotrichum clavatum were the most susceptible of the fungi to GM 237354, with MICs ranging from ≤0.25 to 2 μg/ml. The MICs of GM 237354 against Trichosporon beigelii and the zygomycetesAbsidia corymbifera, Cunninghamella bertholletiae, and Rhizopus arrhizus ranged from ≤0.25 to 8 μg/ml. Against dermatophytes, GM 237354 MICs were ≥2 μg/ml. In summary, we concluded that some sordarin derivatives, such as GM 222712 and GM 237354, showed excellent in vitro activities against a wide range of pathogenic fungi, includingCandida spp., Cryptococcus neoformans, P. carinii, and some filamentous fungi and emerging invasive fungal pathogens.

Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors

2020 ◽  
Vol 20 (18) ◽  
pp. 1628-1639
Author(s):  
Sergi Gómez-Ganau ◽  
Josefa Castillo ◽  
Andrés Cervantes ◽  
Jesus Vicente de Julián-Ortiz ◽  
Rafael Gozalbes
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Binding Affinity ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Significant Activity ◽  
Epidermal Growth

Background: The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma. Methods: We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines. Results: The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib. Conclusion: Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.

Transgenic expression of gallerimycin, a novel antifungal insect defensin from the greater wax moth Galleria mellonella, confers resistance to pathogenic fungi in tobacco

2006 ◽  
Vol 387 (5) ◽  
pp. 549-557 ◽  
Author(s):  
Gregor Langen ◽  
Jafargholi Imani ◽  
Boran Altincicek ◽  
Gernot Kieseritzky ◽  
Karl-Heinz Kogel ◽  
...  
Keyword(s):  
Transgenic Tobacco ◽  
Fungal Pathogens ◽  
Galleria Mellonella ◽  
Ectopic Expression ◽  
Pathogenic Fungi ◽  
Transgenic Expression ◽  
Greater Wax Moth ◽  
Insect Defensin ◽  
Wax Moth

Abstract A cDNA encoding gallerimycin, a novel antifungal peptide from the greater wax moth Galleria mellonella, was isolated from a cDNA library of genes expressed during innate immune response in the caterpillars. Upon ectopic expression of gallerimycin in tobacco, using Agrobacterium tumefaciens as a vector, gallerimycin conferred resistance to the fungal pathogens Erysiphe cichoracearum and Sclerotinia minor. Quantification of gallerimycin mRNA in transgenic tobacco by real-time PCR confirmed transgenic expression under control of the inducible mannopine synthase promoter. Leaf sap and intercellular washing fluid from transgenic tobacco inhibited in vitro germination and growth of the fungal pathogens, demonstrating that gallerimycin is secreted into intercellular spaces. The feasibility of the use of gallerimycin to counteract fungal diseases in crop plants is discussed.

scholarly journals Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nivea Pereira de Sa ◽  
Adam Taouil ◽  
Jinwoo Kim ◽  
Timothy Clement ◽  
Reece M. Hoffmann ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Rational Design ◽  
Antifungal Agents ◽  
Pathogenic Fungus ◽  
Pathogenic Fungi ◽  
Growth Defect ◽  
Wild Type ◽  
Secondary Infections ◽  
Heavy Burden

AbstractPathogenic fungi exhibit a heavy burden on medical care and new therapies are needed. Here, we develop the fungal specific enzyme sterylglucosidase 1 (Sgl1) as a therapeutic target. Sgl1 converts the immunomodulatory glycolipid ergosterol 3β-D-glucoside to ergosterol and glucose. Previously, we found that genetic deletion of Sgl1 in the pathogenic fungus Cryptococcus neoformans (Cn) results in ergosterol 3β-D-glucoside accumulation, renders Cn non-pathogenic, and immunizes mice against secondary infections by wild-type Cn, even in condition of CD4+ T cell deficiency. Here, we disclose two distinct chemical classes that inhibit Sgl1 function in vitro and in Cn cells. Pharmacological inhibition of Sgl1 phenocopies a growth defect of the Cn Δsgl1 mutant and prevents dissemination of wild-type Cn to the brain in a mouse model of infection. Crystal structures of Sgl1 alone and with inhibitors explain Sgl1’s substrate specificity and enable the rational design of antifungal agents targeting Sgl1.

scholarly journals A novel nano-sulphur and essential oil-based room freshener

2021 ◽  
pp. 75-82
Author(s):  
Ashwini S. Kaware ◽  
Pramod U Ingle ◽  
Aniket K. Gade ◽  
Mahendra Rai
Keyword(s):  
Fungal Pathogens ◽  
Indoor Environment ◽  
Toxic Substances ◽  
Significant Activity ◽  
Face Centered Cubic ◽  
Candida Spp ◽  
Indoor Fungi ◽  
The Face ◽  
Average Size

Introduction: Alternaria spp. and Candida spp. are the main fungal pathogen of indoor environment like house, office, classroom, etc. These may cause various diseases and infections like systemic infections, or chronic asthma in immunocompromised individuals through secretion of various toxic substances. Chemical-based commercially available room fresheners used to control the fungal load of indoor environment are not beneficial to human health. Objective: was to provide viable alternative in the form of nanoparticle-based approach for the management of air-borne fungi. Methodology: The present study primarily focuses on the isolation, microscopic and biochemical identification of indoor fungi; Azadirachta indica-mediated sulphur nanoparticles (SNPs) synthesis, their detection and characterization; and in vitro assessment of SNPs against isolated fungi present in indoor environment. Result: The isolated fungi were identified as Alternaria spp and Candida spp. The SNPs showed absorbance maxima at 291 nm. NTA analysis showed average size of 188.4 nm, and zeta potential of -4.94 mV which represented synthesis of stable SNPs. XRD pattern confirmed the face centered cubic, crystalline nature of SNPs. FTIR spectrum depicted the presence of polyhydroxyl, nitrile, keto, aromatic and carboxylic compounds which stabilized the SNPs. The antifungal assays demonstrated the significant activity of the formulated SNPs and eucalyptus oil infused air freshener. Conclusion: It can be concluded that A. indica-mediated SNPs can be applied in the formulation and manufacture of an ecofriendly air freshener for the management of indoor fungal pathogens like Alternaria spp. and Candida spp.

scholarly journals Synthesis, Characterization and in Vitro Antifungal Effect of Some Butyltin(IV) N-substituted 2-aminoethanethiolates

2001 ◽  
Vol 8 (3) ◽  
pp. 165-169 ◽  
Author(s):  
A. Smicka ◽  
V. Buchta ◽  
K. Handlir
Keyword(s):  
Candida Glabrata ◽  
Pathogenic Fungi ◽  
Trichophyton Mentagrophytes ◽  
Candida Krusei ◽  
Antifungal Drugs ◽  
Antifungal Effect ◽  
Absidia Corymbifera ◽  
Structure Activity ◽  
Trichosporon Beigelii

Six new N-substituted di- and tributyltin 2-aminoethanethiolates (cysteaminates) have been prepared and characterised by H1, C13 and S119n NMR spectroscopy. All these compounds exhibit a good in vitro antifungal effect against selected types of human pathogenic fungi (Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, Trichosporon beigelii, Aspergillus fumigatus, Absidia corymbifera, Trichophyton mentagrophytes) and their activity is comparable with that of some antifungal drugs commonly used in the clinical use like ketoconazole. The structure-activity relationships in these compounds are discussed.

scholarly journals Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box

mSphere ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Eric H. Jung ◽  
David J. Meyers ◽  
Jürgen Bosch ◽  
Arturo Casadevall
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogens ◽  
Pathogenic Fungi ◽  
Cryptococcus Gattii ◽  
Antifungal Drugs ◽  
Resistant Bacteria ◽  
Animal Cells ◽  
Malaria Box

ABSTRACTSimilarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity. Consequently, there is a need for new and more effective antifungal drugs. We have identified compounds with significant antifungal activity in the Malaria Box (Medicines for Malaria Ventures, Geneva, Switzerland) that have higher efficacy than some of the currently used antifungal drugs. Our best candidate, MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline), here referred to as DM262, showed 16- to 32-fold-higher activity than fluconazole againstCryptococcus neoformans. There was also significant antifungal activity in other fungal species with known antifungal resistance, such asLomentospora prolificansandCryptococcus gattii. Antifungal activity was also observed against a common fungus,Candida albicans. These results are important because they offer a potentially new class of antifungal drugs and the repurposing of currently available therapeutics.IMPORTANCEMuch like the recent increase in drug-resistant bacteria, there is a rise in antifungal-resistant strains of pathogenic fungi. There is a need for novel and more potent antifungal therapeutics. Consequently, we investigated a mixed library of drug-like and probe-like compounds with activity inPlasmodiumspp. for activity against two common fungal pathogens,Cryptococcus neoformansandCandida albicans, along with two less common pathogenic species,Lomentospora prolificansandCryptococcus gattii. We uncover a previously uncharacterized drug with higher broad-spectrum antifungal activity than some current treatments. Our findings may eventually lead to a compound added to the arsenal of antifungal therapeutics.

In vitro antimicrobial and preliminary phytochemical screening of some Samburu Anti‐diarrhoeal medicinal plants ‐ Kenya

2012 ◽  
Vol 2 (5) ◽  
pp. 217-226
Author(s):  
E. O. Omwenga ◽  
P. O. Okemo ◽  
P. K. Mbugua
Keyword(s):  
Antimicrobial Activity ◽  
Medicinal Plants ◽  
Fungal Pathogens ◽  
Antimicrobial Effect ◽  
Significant Activity ◽  
Bacterial Strains ◽  
Fungal Strains ◽  
Local Isolate ◽  
Agar Disc

The antimicrobial effect of some selected Samburu medicinal plants was evaluated on bacterial strains like Staphylococcus aureus ‐ ATCC 20591, Bacillus subtillis ‐ Local isolate, Salmonella typhi‐ATCC 2202, Escherichia coli‐STD. 25922 and Pseudomonas aeroginosa ‐ ATCC 25852 and fungal strains like Candida albicans ATCC EK138, Aspergillus niger ATCC 16404, Aspergillusflavus‐Local isolate, Fusarium lateritium‐Local isolate, and Penicillium spp.‐ local isolate. Methanol was used as solvent for the extraction from the selected medicinal plants used by the Samburu community. The in vitro antimicrobial activity was performed by agar disc diffusion and micro‐dilution technique. The most susceptible Gram‐positive bacterium was S. aureus, while the most susceptible Gram‐negative bacterium was P. aeroginosa. The extracts of Gomphocarpus fruticosus (L) W.T. Aiton showed less activity against the bacterial strains investigated. The most active antibacterial plants were Euphorbia scarlatica S. Carter, and Euclea divinoram Hiern. Incidentally most of the extracts were inactive against the fungal strains with only a few proving to be slightly active against the C. albicans i.e. Loranthus acaciae Zucc., Kedrostis pseudogijef (Gilg) C. Jeffrey, Euclea divinoram Hiern. and Croton macrostachyus (A. Rich). Benths. The significant antimicrobial activity of active extracts was compared with the standard antimicrobials, cefrodoxima, amoxicillin and fluconazole. The MICs of the most active plants ranged from 18.75mg/ml to 37.50mg/ml. The MBCs ranged between 18.75mg/ml to75mg/ml. These results were significant at P< 0.01. The findings show that most of the medicinal plants used by the Samburu community have some significant activity on the bacterial but not fungal pathogens known to cause diarrhoea.

ISOLATION, IDENTIFICATION AND CHARACTERIZATION OF BACTERIAL ANTAGONISTS OF THE DRAGON FRUIT FUNGAL PATHOGEN Neoscytalidium dimidiatum

2021 ◽  
Vol 44 (02) ◽  
Author(s):  
NGUYEN NGOC AN ◽  
HUA HUYNH MINH THAO ◽  
HO NGUYEN HOANG YEN ◽  
NGUYEN THI DIEU HANH ◽  
NGUYEN LE HIEN HOA ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Pathogenic Fungi ◽  
Fungal Spore ◽  
Stem Canker ◽  
Antagonistic Effect ◽  
Fruit Rot ◽  
Economic Losses ◽  
Neoscytalidium Dimidiatum ◽  
Dragon Fruit

Dragon fruit or pitahaya (Hylocereus spp.) are famous for their nutrient-rich favourable taste, which brings high economic value to subtropical and tropical countries. However, dragon fruit cultivation all over the world is threatened by fungal pathogens and among them, Neoscytalidium dimidiatum has recently been shown to be responsible for stem canker and fruit rot which cause big economic losses. In order to find an environmentally friendly way to control this pathogen, five out of sixty-nine bacterial isolates used in a screening test for antifungal activity were selected. All five strains appeared to be aerobic Gram positive spore forming bacteria suggesting that they all belong to the Bacillus genus. Cell-free culture supernatants of these strains were found to strongly inhibit both fungal spore germination and mycelia growth in vitro for at least 5 days. The strain D19 which possessed the highest antagonistic effect was further identified to be Bacillus amyloliquefaciens, a well-known species shown to have antifungal effect against several other pathogenic fungi. Thus, the results of this study opened a new promising perspective to prevent Neoscytalidium dimidiatum infection during cultivation of dragon fruit.

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