Tea polyphenol epigallocatechin-3-gallate inhibits ergosterol synthesis by disturbing folic acid metabolism in Candida albicans (original) (raw)
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Antimicrobial Agents and Chemotherapy, 2003
Azoles target the ergosterol biosynthetic enzyme lanosterol 14␣-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately, azoles are generally fungistatic and resistance to fluconazole is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of Candida albicans during the membrane stress exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to azoles. Here we establish that drugs targeting other enzymes in the ergosterol biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic synergistic antifungal activity against wild-type C. albicans when used in conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or terbinafine against wild-type C. albicans. These drug combinations also exert synergistic effects against two other Candida species, C. glabrata and C. krusei, which are known for intrinsic or rapidly acquired resistance to azoles. These studies demonstrate that the activity of non-azole antifungal agents that target ergosterol biosynthesis can be enhanced by inhibition of the calcineurin signaling pathway, extending their spectrum of action and providing an alternative approach by which to overcome antifungal drug resistance.
Nature Precedings, 2011
The ERG proteins and enzymes of the ergosterol biosynthetic pathway has been the subject of intensive investigation as a target for several classes of antifungal agents used to treat C. albicans infection. Over the past few decades, a number of drugs and inhibitors with wide spectrum of activity, low toxicity and defined targets have been introduced. Several lines of evidence suggest that allylamines targets squalene epoxidase (ERG1), morpholines affects sterol C8-C7 isomerase (ERG2) and sterol reductase (ERG24), azoles inhibits a cytochrome P450 (ERG11) responsible for the 14 α-demethylation of lanosterol and C-5 sterol desaturase (ERG3) and polyenes binds to ergosterol that leads to the damage of cell plasma membrane, ensuing in leakage of intracellular ions. However, little information about the experimental structure (X-ray and NMR) of proteins from ergosterol biosynthetic pathway is available in RCSB Protein Databank (PDB). Since ERG proteins play a key role in metabolic pathwa...
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.
Antimicrobial Agents and Chemotherapy, 2004
R126638 is a novel triazole with in vitro activity similar to that of itraconazole against dermatophytes, Candida spp., and Malassezia spp. In animal models of dermatophyte infections, R126638 showed superior antifungal activity. R126638 inhibits ergosterol synthesis in Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Microsporum canis at nanomolar concentrations, with 50% inhibitory concentrations (IC 50 s) similar to those of itraconazole. The decreased synthesis of ergosterol and the concomitant accumulation of 14␣-methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14␣-methyl group of lanosterol or eburicol. The IC 50 s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 M for itraconazole and 3.1 M for R126638. Compared to itraconazole (IC 50 ؍ 3.5 M), R126638 is a poor inhibitor of the 1␣-hydroxylation of 25-hydroxyvitamin D 3 (IC 50 > 10 M). Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D 3 and the conversion of 1,25-dihydroxyvitamin D 3 into polar metabolites. At concentrations up to 10 M, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11hydroxylase (CYP11B1), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26). At 10 M, R126638 did not show clear inhibition of CYP1A2, CYP2A6, CYP2D6, CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1. Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6 hydroxylation and cyclosporine hydroxylation, both of which are catalyzed by CYP3A4, whereas both antifungals inhibited the CYP3A4-catalyzed hydroxylation of midazolam similarly. The results suggest that R126638 has promising properties and merits further in vivo investigations for the treatment of dermatophyte and yeast infections. R126638 (Fig.
2015
The emergence of antibiotic resistance in pathogeni c Candida species has led to explore new alternativ e therapies to combat its associated life threatening infection s. Synergistic anticandidal potentials of green tea (derived from Camellia sinensis) with antifungal agents is well k nown. Our study aims at predicting the novel inhibi tory targets of green tea (GT) phytocompounds and pretending the in ibitory mechanism involved in synergistic inhibiti on of GT with antifungals. The interaction of GT phytocompou nds and ergosterol synthesising proteins (ERG) of t he Candida species has been assessed by in silico study using iGEMDOCK software which revealed ERG 26, ERG 6, ERG 25, and ERG 8 proteins as novel drug targets of kaempfe ritrin, EGCG, ECG, chlorogenic acid respectively pr esent in GT.Supporting our investigation, in vitro studies h ave been done with GT leaves from different geograp hic l locations. Catechins were purified and identified b y HPLC and synergistic effect of s...
2021
ABSTRACTDue to the emergence of multi-drug resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase (CgHMGR), and thus affect ergosterol synthesis and yeast viability. One series of synthetic antifungal compounds were analogues to fibrates, a second series had substituted 1,2-dihydroquinolines and the third series included substituted pyrroles. α-asarone-related compounds 1c and 5b with a pyrrolic core were selected as the best antifungal candidates. Both inhibited the growth of fluconazole-resistant C. glabrata 43 and fluconazole-susceptible C. glabrata CBS 138. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway...
An Antifungal Benzimidazole Derivative Inhibits Ergosterol Biosynthesis and Reveals Novel Sterols
Antimicrobial Agents and Chemotherapy, 2015
Fungal infections are a leading cause of morbidity and death for hospitalized patients, mainly because they remain difficult to diagnose and to treat. Diseases range from widespread superficial infections such as vulvovaginal infections to life-threatening systemic candidiasis. For systemic mycoses, only a restricted arsenal of antifungal agents is available. Commonly used classes of antifungal compounds include azoles, polyenes, and echinocandins. Due to emerging resistance to standard therapies, significant side effects, and high costs for several antifungals, there is a need for new antifungals in the clinic. In order to expand the arsenal of compounds with antifungal activity, we previously screened a compound library using a cell-based screening assay. A set of novel benzimidazole derivatives, including (S)-2-(1-aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole (EMC120B12), showed high antifungal activity against several species of pathogenic yeasts, includingCandida glabrataandCa...
Journal of clinical microbiology, 1999
MIC end points for the most commonly prescribed azole antifungal drug, fluconazole, can be difficult to determine because its fungistatic nature can lead to excessive "trailing" of growth during susceptibility testing by National Committee for Clinical Laboratory Standards broth macrodilution and microdilution methods. To overcome this ambiguity, and because fluconazole acts by inhibiting ergosterol biosynthesis, we developed a novel method to differentiate fluconazole-susceptible from fluconazole-resistant isolates by quantitating ergosterol production in cells grown in 0, 1, 4, 16, or 64 microg of fluconazole per ml. Ergosterol was isolated from whole yeast cells by saponification, followed by extraction of nonsaponifiable lipids with heptane. Ergosterol was identified by its unique spectrophotometric absorbance profile between 240 and 300 nm. We used this sterol quantitation method (SQM) to test 38 isolates with broth microdilution end points of </=8 microg/ml (susce...