Prediction of novel drug targets in Ergosterol biosynthesis pathway: A proposed mechanism of anticandidal activity of gr een tea phytocompounds (original) (raw)
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International Journal of Research in Pharmaceutical Sciences
Green tea is credited as one of the world’s healthiest drinks with enriched antioxidants. It is known for its multi-beneficial health benefits against diabetes, blood pressure, hypertension, gastro-intestinal upset and is bestowed with significant antimicrobial potential. There are previous scientific evidence highlighting the antifungal potential of green tea and has identified it as a potential inhibitor of non-albicans Candida species. Lansterol 14-α demethylase (Erg 11) or CYP51 protein belongs to the cytochrome P450 monooxygenase (CYP) superfamily. Erg 11 is involved in ergosterol biosynthesis and has a significant role in azole drug resistance in Candida glabrata. The present study attempted to identify the inhibitory potential of green tea phytocompounds against inhibition of Erg 11 in Candida glabrata using bioinformatics tool viz., autodock vina software. Out of 15 green tea phytocompounds investigated, the study identified, Rutin (-10.5 kcal) Kaempferitrin (-9.4kcal), Epig...
Journal of Antimicrobial Chemotherapy, 2006
Elucidation of the mechanism of action of epigallocatechin-3-gallate (EGCG) against Candida albicans and demonstration of the connection between its antifolate activity and other metabolic pathways involved in C. albicans survival are the major objectives of this study. Methods: C. albicans ATCC 10231 and 12 clinical isolates were used. MICs of EGCG against C. albicans were determined according to NCCLS. C. albicans dihydrofolate reductase (DHFR) was purified using methotrexate-affinity chromatography and its inhibition by EGCG studied by spectroscopic techniques. Synergy experiments were performed by chequerboard tests by combining eight doubling concentrations of EGCG with another eight dilutions of azole compounds or terbinafine. Reversion experiments with leucovorin or S-adenosylmethionine were carried out, and the content of ergosterol was determined by a spectrophotometric method. Results: EGCG is an efficient inhibitor of C. albicans DHFR (K i = 0.7 mM). As with other antifolates, the effects of EGCG on C. albicans can be highly attenuated by growing the cells in the presence of leucovorin. EGCG showed synergy with inhibitors of the ergosterol biosynthesis pathway in C. albicans such as azole antifungals and terbinafine. We demonstrate that by disturbing the folate metabolism, EGCG can inhibit ergosterol production. The molecular connection between the pathways is discussed. Conclusions: EGCG acts as an antifolate compound on C. albicans, disturbing its folic acid metabolism. This effect could explain the molecular mechanism for the synergy between EGCG and azole antifungals, and could represent a starting point for therapies involving antifolates and azoles used as an alternative for the treatment of C. albicans infections.
Antimycotic activity of green tea phytocompounds against Candida glabrata
Environment Conservation Journal, 2023
One of the medically important opportunistic fungal pathogen for humans is Candida glabrata that causes various types of candidiasis. Its environmental adaptations and antimicrobial resistance is now a great concern for public health. In the present study, the green tea phytocompounds; EGCg, Chlorogenic acid, Coumaroyl quinic acid and Rutin trihydrate along with a known antimycotic Fluconazole were studied for their antimycotic activity against Candida glabrata. The MIC90 for C. glabrata was observed at 125µg/ml for EGC g, 250 µg/mlf or Chlorogenic acid, 500µg/ml for Coumaroyl quinic acid and Rutin trihydrate while 12.5µg/ml for Fluconazole in macro dilution assay while the MFC values were 1000 µg/ml for EGC g, 500 µg/ml for Chlorogenic acid, Coumaroyl quinic acid, Rutin trihydrate and 50 µg/ml for Fluconazole. In microdilution assay, the MIC90 for C. glabrata was observed 125µg/ml for EGC g and chlorogenic acid, 500µg/ml for Coumaroyl quinic acid, Rutin trihydrate and 12.5µg/ml for Fluconazole while the MFC values were 31.25 µg/ml for Fluconazole, 250 µg/ml for chlorogenic acid and 500 µg/ml for EGC g, Coumaroyl quinic acid and Rutin trihydrate. EGCg and Chlorogenic acid was found to be more effective against C. glabrata and therefore these two were used for synergistic study along with Fluconazole. The viability of HeLa cells (in per cent) was observed ≥100% green tea phyto compounds. The viability of treated cells (in per cent) with a combination of Green tea, phytocompounds and fluconazole was observed between ≥98± 0.79 to ≥ 98± 0.87. Green tea phytocompounds mainly EGC g and chlorogenic acid can be used as synergistic molecules having antimycotic activity against C. glabrata. India has one of the highest incidences of blood stream Candida infections worldwide (Gaffi-Global Action For Fungal Infections). About 35 to 40% of C. tropicalis species have been reported from clinical specimens like blood, urine, sputum, pus, lung aspirate, catheter tips, nail, throat swab, tested in patients in north India (Singh et al., 2011;
Evolution of ergosterol biosynthesis inhibitors as fungicidal against Candida
Microbial Pathogenesis, 2010
Azoles target the ergosterol synthesizing enzyme lanosterol 14a-demethylase and are a widely applied class of antifungal agents. Unfortunately azoles are generally fungistatic, and resistance to fluconazole is emerging in several fungal pathogens. In contrast to the increasing number of agents for the treatment of invasive fungal infections, discoveries of new antifungal agents with therapeutic value in dermatomycoses are reported only rare. Attention has been drawn to the antimicrobial activity of plants and their active principles due to the challenge of growing incidences of drug-resistant pathogens. Eugenol and methyl eugenol were reported to possess antimycotic properties. To further explore the antifungal activity of these compounds, in vitro studies were conducted on various Candida isolates. Insight studies to mechanism suggested that both eugenol and methyl eugenol exerts their antifungal activity by targeting sterol biosynthesis. Furthermore, it was also observed that additional methyl group to eugenol increases its antifungal activity. The observed fungicidal characteristics of both eugenol and methyl eugenol indicate that both the compounds might be promising antifungal agents defining a new class of antimycotics.
Small molecules inhibit growth, viability and ergosterol biosynthesis in Candida albicans
SpringerPlus, 2013
The aim of this work was to evaluate the anti-Candida efficacy of twenty five molecules of plant origin. Based on their MICs, effective molecules were categorized into four categories. Susceptibility testing of test compounds was carried out by standard methodology (M27-A2) as per CLSI guidelines. Minimum Fungicidal Concentration (MFC) was determined as the lowest concentration of drug killing 99.9 % cells. Effect on sterol profile was evaluated by sterol quantitation method. Among the screened molecules, cinnamaldehyde, piperidine, citral, furfuraldehyde and indole were potent inhibitors of growth and viability. Exposure of Candida cells to cinnamaldehyde, piperidine, citral, furfuraldehyde, indole, αand βpinene at MIC's, altered ergosterol profile. Our results indicate that the molecules altering sterol profile may exert their antifungal effect through inhibition of ergosterol biosynthesis and could be good candidates for fungal specific drug development.
Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens
Antimicrobial agents and chemotherapy, 2017
Candida albicans is a major cause of fungal diseases in humans, and its resistance to available drugs is of concern. In an attempt to identify novel antifungal agents, we initiated a small-scale screening of a library of 199 natural plant compounds (i.e., natural products [NPs]). In vitro susceptibility profiling experiments identified 33 NPs with activity against C. albicans (MIC50s ≤ 32 μg/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from the tomato (Solanum lycopersicum) and exhibited high levels of fungistatic activity against Candida species (MIC50s ≤ 1 μg/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of tomatidine-treated C. albicans cells revealed a major alteration (upregulation) in the expression of ergosterol genes, suggesting that the ergosterol pathway is targeted by this NP. Consistent with this transcriptional response, analysis of the sterol content of tomatidine-tre...
The Effects of Combretum zeyheri Leaf Extract on Ergosterol Synthesis in Candida albicans
Journal of Herbs, Spices & Medicinal Plants, 2014
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Journal de Mycologie Médicale, 2017
The present investigation aims at evaluating synergistic herbal based composition of purified catechins with fluconazole, amphotericin B and copper sulphate against Candida albicans (MTCC 3017) and Candida glabrata (MTCC 3019). The catechins were isolated from green tea leaves of Assam, Himachal Pradesh and Uttarakhand regions of India. The synergistic activity of combinations against Candida species was assessed following microdilution checkerboard technique and time kill assay. The inhibitory action of most significant combination on treated Candida cells was assessed by scanning electron microscopy. Cytotoxicity of synergistic compositions was further analyzed by performing MTT assay on Vero cell lines. Purified catechins of Assam and Himachal Pradesh green tea showed synergistic activity with fluconazole and amphotericin B against Candida species. Time kill assay depicted synergistic activity at minimum inhibitory concentration and twice of minimum inhibitory concentration of purified catechins and antimycotics. Further, Copper sulphate increased anticandidal efficacy of synergistic
Molecular Plant-Microbe Interactions®, 2021
Diseases caused by fungi can affect the quality and yield of the leaves of tea [Camellia sinensis (L.) Kuntze]. At present, the availability of highly effective and safe fungicides for controlling tea plants remains limited. The objectives of this study were to identify novel compounds with antifungal activities and to determine their molecular mechanisms. A series of sulfone compounds containing 1,3,4-oxadiazole were evaluated in China for their antifungal activities against several pathogens causing foliar diseases and high production losses. Transcriptomics and bioinformatics were used to analyze the differentially expressed genes of Lasiodiplodia theobromae treated with a representative compound, jiahuangxianjunzuo (JHXJZ). Moreover, the effects of JHXJZ on ergosterol content, membrane permeability, cell structure, and seven key genes involved in the ergosterol biosynthetic pathway were investigated. JHXJZ had a strong antifungal activity against L. theobromae in vitro, with an ...