scholarly journals Rapamycin and Less Immunosuppressive Analogs Are Toxic to Candida albicans and Cryptococcus neoformans via FKBP12-Dependent Inhibition of TOR

2001 ◽  
Vol 45 (11) ◽  
pp. 3162-3170 ◽  
Author(s):  
M. Cristina Cruz ◽  
Alan L. Goldstein ◽  
Jill Blankenship ◽  
Maurizio Del Poeta ◽  
John R. Perfect ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Immunosuppressive Drug ◽  
Mutant Strains ◽  
Dependent Inhibition ◽  
Tor Kinase ◽  
Mutant Kinase

ABSTRACT Candida albicans and Cryptococcus neoformans cause both superficial and disseminated infections in humans. Current antifungal therapies for deep-seated infections are limited to amphotericin B, flucytosine, and azoles. A limitation is that commonly used azoles are fungistatic in vitro and in vivo. Our studies address the mechanisms of antifungal activity of the immunosuppressive drug rapamycin (sirolimus) and its analogs with decreased immunosuppressive activity. C. albicans rbp1/rbp1 mutant strains lacking a homolog of the FK506-rapamycin target protein FKBP12 were found to be viable and resistant to rapamycin and its analogs. Rapamycin and analogs promoted FKBP12 binding to the wild-type Tor1 kinase but not to a rapamycin-resistant Tor1 mutant kinase (S1972R). FKBP12 and TOR mutations conferred resistance to rapamycin and its analogs inC. albicans, C. neoformans, andSaccharomyces cerevisiae. Our findings demonstrate the antifungal activity of rapamycin and rapamycin analogs is mediated via conserved complexes with FKBP12 and Tor kinase homologs in divergent yeasts. Taken together with our observations that rapamycin and its analogs are fungicidal and that spontaneous drug resistance occurs at a low rate, these mechanistic findings support continued investigation of rapamycin analogs as novel antifungal agents.

Spilanthol as a promising antifungal alkylamide for the treatment of vulvovaginal candidiasis

2021 ◽  
Author(s):  
Rodrigo L Fabri ◽  
Jhamine C O Freitas ◽  
Ari S O Lemos ◽  
Lara M Campos ◽  
Irley O M Diniz ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Cell Membrane ◽  
Multidrug Resistant ◽  
Fungal Strain ◽  
Vulvovaginal Candidiasis ◽  
Biofilm Matrix

Abstract Spilanthol is a bioactive alkylamide from the native Amazon plant species, Acmella oleracea. However, antifungal activities of spilanthol and its application to the therapeutic treatment of candidiasis remains to be explored. This study sought to evaluate the in vitro and in vivo antifungal activity of spilanthol previously isolated from A. oleracea (spilanthol(AcO)) against Candida albicans ATCC® 10231™, a multidrug-resistant fungal strain. Microdilution methods were used to determine inhibitory and fungicidal concentrations of spilanthol(AcO). In planktonic cultures, the fungal growth kinetics, yeast cell metabolic activity, cell membrane permeability and cell wall integrity were investigated. The effect of spilanthol(AcO) on the proliferation and adhesion of fungal biofilms was evaluated by whole slide imaging and scanning electron microscopy. The biochemical composition of the biofilm matrix was also analyzed. In parallel, spilanthol(AcO) was tested in vivo in an experimental vulvovaginal candidiasis model. Our in vitro analyses in C. albicans planktonic cultures detected a significant inhibitory effect of spilanthol(AcO), which affects both yeast cell membrane and cell wall integrity, interfering with the fungus growth. C. albicans biofilm proliferation and adhesion, as well as, carbohydrates and DNA in biofilm matrix were reduced after spilanthol(AcO) treatment. Moreover, infected rats treated with spilanthol(AcO) showed consistent reduction of both fungal burden and inflammatory processes compared to the untreated animals. Altogether, our findings demonstrated that spilanthol(AcO) is an bioactive compound against planktonic and biofilm forms of a multidrug resistant C. albicans strain. Furthermore, spilanthol(AcO) can be potentially considered for therapeutical treatment of vulvovaginal candidiasis caused by C. albicans. Lay Abstract This study sought to evaluate the antifungal activity of spilanthol against Candida albicans ATCC® 10 231™, a multidrug-resistant fungal strain. Our findings demonstrated that spilanthol(AcO) can be potentially considered for therapeutical treatment of vulvovaginal candidiasis caused by C. albicans.

scholarly journals Antifungal Activity of the Essential Oil of Echinops kebericho Mesfin: An In Vitro Study

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Tamirat Bekele Beressa ◽  
Serawit Deyno ◽  
Paul E. Alele
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Essential Oil ◽  
Cryptococcus Neoformans ◽  
Antioxidant Properties ◽  
Pathogenic Fungi ◽  
Diffusion Method ◽  
Potential Candidate ◽  
Standard Drug

Background. Echinops kebericho is an endemic medicinal plant in Ethiopia widely used in the treatment of infectious and noninfectious diseases. Essential oils are known for their antibacterial, antifungal, antiviral, insecticidal, and antioxidant properties. This study evaluated the antifungal activity of essential oil from E. kebericho against four common pathogenic fungi and two standard strains. Methods. The essential oil was obtained by hydrodistillation. The antifungal screening was done by agar well diffusion method. Minimal inhibitory concentrations (MICs) were determined by broth microdilution. Minimal fungicidal concentrations (MFCs) were determined by subculturing fungal strains with no visible growth onto a Sabouraud dextrose agar (SDA) plate. Results. Candida albicans and Cryptococcus neoformans were highly sensitive while Aspergillus flavus did not show sensitivity up to 1 mg/ml of essential oil; MICs ranged from 0.083 mg/ml to 0.208 mg/ml. Concentration and fungal species showed significant dose-dependent associations ( p < 0.0001 ) with antifungal activity. The MICs of essential oil were comparable to those of the standard drug (fluconazole) against C. glabrata and C. krusei. The lowest MFC of the essential oil was observed against Candida parapsilosis (0.145 mg/ml) while the highest MFC was against Candida krusei (0.667 mg/ml). Conclusion. Echinops kebericho essential oil showed noteworthy antifungal activity against Cryptococcus neoformans, Candida albicans, and Candida glabrata and could be a potential candidate for further antifungal drug development.

scholarly journals Antifungal activity of Ocimum gratissimum L., Lantana camara L. & Pteleopsis suberosa Engl. & Dies used in the treatment of vulvovaginal candidiasis in Benin

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jean Robert Klotoe ◽  
Brice Armand Fanou ◽  
Eric Agbodjento ◽  
Arnaud Houehou ◽  
Lauris Fah ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Aqueous Extract ◽  
Lantana Camara ◽  
Vulvovaginal Candidiasis ◽  
Reference Drug ◽  
Clinical Strains ◽  
Ocimum Gratissimum

Abstract Background Vulvovaginal candidiasis is a widespread mycotic infection that affects a large proportion of women of childbearing age. Its management in traditional medicine is based on the use of medicinal plants. This study aimed to evaluate the antifungal activity of Ocimum gratissimum L., Lantana camara L. and Pteleopsis suberosa Engl. & Diels used in the treatment of vulvovaginal candidiasis in Benin. Results The data obtained from the in vitro antifungal test show that the strains tested (ATCC 90028 and two clinical strains: 1MA and 3MA) were more sensitive to aqueous extracts with a better effect for Pteleopsis suberosa. This potential of the tested extracts correlated with their richness in total polyphenols. The extract of the Pteleopsis suberosa was very active on the inhibition of the reference strain ATCC 90028. On the clinical strains (1MA and 3MA) the aqueous extract of Pteleopsis suberosa showed a better MIC on the 1MA strain. In vivo model, inoculation of 100 µL of the concentrated Candida albicans suspension 1.5 × 105 UFC/mL induced the candidiasis of the female Wistar rat. The treatment with the aqueous extract of Pteleopsis suberosa, like fluconazole (reference drug), significantly reduced Candida albicans infection at a dose of 100 mg/kg after 1, 7 and 13 days of treatment. Conclusion This study revealed the potential antifungal of the Ocimum gratissimum, Lantana camara and Pteleopsis suberosa. Pteleopsis suberosa has better antifungal activity in vitro and in vivo. These observations justify the use of their medicinal plant in the traditional treatment of vulvovaginal candidiasis in Benin.

scholarly journals study the effect of alcoholic and watery extracts of garlic and onion plants on growth of candida albicans and Cryptococcus neoformans in vitro&vivo

2008 ◽  
Vol 32 (2) ◽  
pp. 29-38
Author(s):  
Abd-Alshaheed D. A.
Keyword(s):  
Candida Albicans ◽  
Cryptococcus Neoformans ◽  
Included Study ◽  
Control Group ◽  
Alcoholic Extract ◽  
Ofcandida Albicans ◽  
Group 3 ◽  
Group 2

This research included study the effect of garlic and onion plantsextracts(alcoholic and watery) in vitro in three different concentrations15%,25%,35% and in vivo in experimental white mice .Research wasperformed by three experiments, first one was conducted to studyeffectiveness of different concentration of alcoholic and watery garlicextract on growth of candida albicans and Cryptococcus neoformans invitro, showed that the effect of alcoholic extract on the growth of candidaalbicans was inhibitory,started from 0.4 mm to 0.1 mm compared withcontrol plats 4.2 mm ,where as the results of the effect on the growth ofCryptococcus neoformans showed more clearness and the inhibitionstarted from 0.6 to inhibit all the growth in plat in comparison withcontrol plats1.4 mm. While the effect of watery garlic extract showed lesseffect and the inhibition began from 0.5 mm to 0.2 mm for candidaalbicans , but the growth inhibition of Cryptococcus neoformans beganfrom 0.4 to 0.15 mm.The second experiment was the same as the firstexperiment , but using alcoholic and extracts onion , the growth ofcandida albicans inhibited by alcoholic exract from 0.6 mm to no growthin the plat , but the inhibition of Cryptococcus neoformans was startedfrom 0.5mm to 0.2 mm for alcoholic onion extract. While the wateryonion extract effect on the growth of candida albicans the inhibitionstarted from 1.6 mm to 1 mm ,but the inhibition of Cryptococcusneoformans was began from 1 mm to 0.3 mm.Third experiment was study the effect of crude garlic and onion alcoholicextract ointment 1% on experimental infection in mice , using 30experimental mice divided to 6 equal groups,each group include 5 mice*groups which infected with candida albicans treated :The group 1,2,3,expermrutly infected with candida albicans ,where asgroup 3,4,6 were infected with Cryptococcus neoformans for 1,2,3 group,treted with the ointment of alcoholic extract of garlic, group 2 treatedwith alcoholic extract ointment of onion, where as group 3 left with notreatment as a control group

scholarly journals Antifungal Activity of Plumericin and Isoplumericin

2011 ◽  
Vol 6 (11) ◽  
pp. 1934578X1100601 ◽  
Author(s):  
Dharmendra Singh ◽  
Umakant Sharma ◽  
Parveen Kumar ◽  
Yogesh K Gupta ◽  
M. P. Dobhal ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Minimum Inhibitory Concentration ◽  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Inhibitory Concentration ◽  
Chloroform Extract ◽  
Drug Candidate ◽  
Minimum Fungicidal Concentration ◽  
In Vitro Antifungal Activity

This study evaluated the in vitro antifungal activity of the chloroform extract of Plumeria bicolor and its phytoconstituents plumericin and isoplumericin against Candida species and Cryptococcus neoformans by measuring the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC). Plumericin's consistently high activity against Candida albicans, C. krusei, C. glabrata, C. tropicalis and Cryptococcus neoformans was more potent than isoplumericin and the standard antifungal drug nystatin suggesting its potential as a drug candidate for candidiasis and cryptococcosis.

In vitro and in vivo activity of chelerythrine against Candida albicans and underlying mechanisms

2019 ◽  
Vol 14 (18) ◽  
pp. 1545-1557 ◽  
Author(s):  
Ying Gong ◽  
Siwen Li ◽  
Weixin Wang ◽  
Yiman Li ◽  
Wenli Ma ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Calcium Concentration ◽  
Galleria Mellonella ◽  
Hyphal Growth ◽  
Drug Transporter ◽  
Antifungal Effect ◽  
Underlying Mechanisms

Aim: To evaluate whether chelerythrine (CHT) exhibited antifungal activity against Candida albicans in vitro and in vivo and to explore the underlying mechanisms. Materials & methods: Broth microdilution assay and Galleria mellonella model were used to evaluate the antifungal effect in vitro and in vivo, respectively. Mechanism studies were investigated by morphogenesis observation, Fluo-3/AM, DCFH-DA and rhodamine6G assay, respectively. Results: CHT exhibited antifungal activity against C. albicans and preformed biofilms with minimum inhibitory concentrations ranged from 2 to 16 μg/ml. Besides, CHT protected G. mellonella larvae infected by C. albicans. Mechanisms studies revealed that CHT inhibited hyphal growth, increased intracellular calcium concentration, induced accumulation of reactive oxygen species and inhibited drug transporter activity. Conclusion: CHT exhibited antifungal activity against C. albicans.

In vitro Antifungal Activity of Dihydropyrimidinones/Thiones Against Candida albicans and Cryptococcus neoformans

2020 ◽  
Vol 15 (6) ◽  
pp. 648-655
Author(s):  
Gabriel O. de Azambuja ◽  
Laura Svetaz ◽  
Itamar L. Gonçalves ◽  
Patricia F. Corbelini ◽  
Gilsane L. von Poser ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Drug Design ◽  
Cryptococcus Neoformans ◽  
Biginelli Reaction ◽  
Fungal Growth ◽  
Chemical Library ◽  
Antifungal Effect ◽  
In Vitro Antifungal Activity

Background: Since the Monastrol discovery in 1999 as the first inhibitor of Eg5, functionalized dihydropyrimidinones/thiones (DHPMs) have emerged as prototypes for drug design in different targets. The present work aimed to evaluate the antifungal activity of a chemical library of DHPMs. Methods: The compounds were obtained employing Biginelli reaction. Their antifungal activities were assessed against C. neoformans and C. albicans. Results: The compounds 1-i and 1-k inhibited moderately the fungal growth of C. neoformans, with compound 2-k presenting MIC80 values of 62.5-125 µg·mL-1. Considering activity against C. albicans, the compounds 1-i and 1-n present an MIC50 value of 125-250 µg·mL-1. Conclusion: The changes performed in DHPM scaffold appear to be valuable for generating compounds with potential antifungal effect.

In vitro antifungal activity of eugenol and vanillin against Candida albicans and Cryptococcus neoformans

1982 ◽  
Vol 28 (11) ◽  
pp. 1235-1241 ◽  
Author(s):  
Chuenchit Boonchird ◽  
T. W. Flegel
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Tube Formation ◽  
Toxicity Tests ◽  
Short Term ◽  
Minimal Inhibitory Concentrations ◽  
The Mean ◽  
In Vitro Antifungal Activity

Eugenol and vanillin were examined for in vitro antifungal activity against the medically important yeasts, Candida albicans and Cryptococcus neoformans. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) were determined for each compound against 31 strains of C. albicans and 33 strains of C. neoformans. With eugenol, the mean MIC's for C. albicans and C. neoformans were 625 and 293 μg/mL, respectively, while the mean MFC's were 1209 and 521 μg/mL, respectively. With vanillin, the mean MIC's for C. albicans and C. neoformans were 1250 and 738 μg/mL, respectively, while the mean MFC's were 5000 and 1761 μg/mL, respectively. With C. albicans, inhibition and retardation of growth were similar for yeast and mycelial forms, but germ tube formation was inhibited at concentrations lower than those which inhibited growth. Short-term toxicity tests with mice using the intraperitoneal route gave maximum tolerated doses of 62.5 mg/kg for eugenol and 125 mg/kg for vanillin and excluded their use as therapeutic agents for systemic mycoses.

In vitro antifungal activity of some Mannich bases of conjugated styryl ketones

1998 ◽  
Vol 44 (1) ◽  
pp. 74-79 ◽  
Author(s):  
Elias K Manavathu ◽  
S C Vashishtha ◽  
George J Alangaden ◽  
Jonathan R Dimmock
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Growth ◽  
Mannich Bases ◽  
Minimum Fungicidal Concentration ◽  
Dependent Inhibition ◽  
Normal Human ◽  
Further Development ◽  
In Vitro Antifungal Activity

Four Mannich bases of some conjugated styryl ketones IIa-IId were examined for antifungal activity. These compounds were designed as thiol-alkylators and had two centers for attack by cellular thiols. The most potent compounds IIa and IIb possessed hydrophobic, electron-attracting substituents in the aryl rings and in general had minimum inhibitory concentration (MIC) values of 0.2-25 μM against a variety of fungi. None of the four compounds inhibited the growth of a number of bacteria (MIC > 100 μM). The minimum fungicidal concentration (MFC) values for IIa and IIb were generally either similar or twofold higher than the MIC figures for fungi. Compound IIa demonstrated rapid, concentration-dependent inhibition of the growth of Candida albicans B311. The toxicity of IIa to normal human cells was much lower than the concentrations of this compound required to inhibit fungal growth. In summary, this study of four prototypic molecules has revealed that this class of compounds may have potential for further development as candidate antifungal agents.Key words: antifungal, styryl ketones, Candida albicans, Aspergillus fumigatus, susceptibility test.

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