Fungal epipolythiodioxopiperazine toxins have therapeutic potential and roles in disease

Jordan, T. William; Cordiner, Stephen J.

doi:10.1016/0165-6147(87)90184-2

Cited by 33 publications

(22 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Weindling and Emerson (1936) Lee et al, 2001) and 1966, respectively (Weindling, 1941;Beecham et al, 1966). During several years there had been confusion about the nomenclature of the gliotoxinproducing fungus (Webster & Lomas, 1964 Antimicrobial activities of gliotoxin isolated in the current study also match with the previous reports (Taylor, 1971;Jordan & Cordiner, 1987). According to reported data of Brian and Hemming (1945), gliotoxin has shown MIC values of 3, 10 and 20 µg mL -1 against S. aureus (NCTC 3750), B. subtilis (NCTC 3610) and E. coli (NCTC 4144), respectively.…”

Section: Discussionsupporting

confidence: 80%

See 1 more Smart Citation

Antimicrobial constituents of Hypocrea virens, an endophyte of the mangrove-associate plant Premna serratifolia L.

Ratnaweera¹,

Silva²,

Wijesundera³

et al. 2016

J. Natn. Sci. Foundation Sri Lanka

View full text Add to dashboard Cite

Emergence of multidrug-resistant pathogenic microorganisms has prompted a worldwide search for new antibiotics from various sources. Endophytic fungi from unique habitats are considered as potential sources of novel bioactive compounds. Sri Lankan mangrove ecosystem is such a distinctive and unexploited resource for the discovery of structurally diverse and biologically active metabolites including antimicrobials. Nine endophytic fungi were isolated from the leaves and twigs of Premna serratifolia L. from a mangrove habitat in the Negombo lagoon and the antimicrobial activities of their laboratory cultures were evaluated. The most promising antimicrobial activity was exhibited by the endophytic fungus Hypocrea virens. Bioassay guided fractionation of the organic extract of this fungus led to the isolation of two known metabolites; the antimicrobial epidithiodioxopiperazine, gliotoxin (1), and the closely related but less active bisdethiobis(methylthio)gliotxin (2). The chemical structures of the two compounds were determined by spectroscopy and confirmed by comparison of mass and nuclear magnetic resonance (NMR) spectral data with the reported values for these molecules. The minimum inhibitory concentration (MIC) values obtained for gliotoxin (1) in the current study are 0.13 µg mL -1 for Bacillus subtilis, 16 µg mL -1 for Staphylococcus aureus, 32 µg mL -1 for Methicillin Resistant Staphylococcus aureus (MRSA) and Escherichia coli, 64 µg mL -1 for Pseudomonas aeruginosa and Candida albicans fungus. This is the first study to report the isolation of endophytic fungi from P. serratifolia and their antimicrobial activities.

show abstract

Section: Discussionsupporting

confidence: 80%

“…Gliotoxin has attracted considerable attention mainly due to its antibacterial, antifungal and antiviral activities (Jordan & Cordiner, 1987). It has also shown selective toxicity to cells of the haematopoietic system (Mullbacher & Eichner, 1984;Mullbacher et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial constituents of Hypocrea virens, an endophyte of the mangrove-associate plant Premna serratifolia L.

Ratnaweera¹,

Silva²,

Wijesundera³

et al. 2016

J. Natn. Sci. Foundation Sri Lanka

View full text Add to dashboard Cite

show abstract

“…In such a long-term study, development of a concurrent infectious disease is a risk, especially with sporidesmin, which has im munosuppressive activity [19]. As WBC re mained unchanged until day 21, all observa tions were related to the toxic effects of spo ridesmin.…”

Section: Haematology and Biochemistrymentioning

confidence: 97%

Liver Enzyme Changes in a Guinea-Pig Model of Facial Eczema (Sporidesmiotoxicosis)

Bonnefoi

Hasim²,

Sauvagnac³

et al. 1989

Enzyme

View full text Add to dashboard Cite

Sporidesmin, a hepatotoxin from Pithomyces chartarum, is responsible for facial eczema in ruminants. In an attempt to clarify the biochemical processes supporting sporidesmin toxicity and response of the liver, haematology, plasma biochemistry and liver enzyme changes were monitored for 21 days in a model for facial eczema resulting from a single intraperitoneal injection of 2.8 mg/kg BW sporidesmin to guinea pigs. Most plasma disturbances were observed 8 days after administration and accounted for starvation, liver cytolysis, and cholestasis or liver enzyme induction. Alterations of hepatic enzyme activities were intense with a maximum increase on days 2 for alkaline phosphatases (ALP) and 8 for γ-glutamyltransferase (GGT), and a maximum decrease on day 21 for aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT). Comparison of liver and plasma enzyme changes indicates that GGT was the most reliable and significant plasma indicator of sporidesmin-associated liver alterations. Moreover, this study points out the validity of the one-dose intoxicated guinea-pig model for research on sporidesmin biochemical toxicity and pathobiology of facial eczema.

show abstract

“…This thioldisulfide interchange reaction is likely crucial for maintaining intracellular thiol status (2-7) under a variety of physiological and pathophysiological processes like aging, cardiovascular and neurodegenerative diseases, AIDS, and cancer chemotherapy where sulfhydryl redox balance is challenged and there is a tendency to accumulate protein-SSG (7)(8)(9)(10)(11). Likewise the intracellular redox balance can be shifted and protein-thiols modified by exogenous disulfides including toxins like sporidesmin (12).…”

mentioning

confidence: 99%

“…Sporidesmin and its analog gliotoxin are among the best characterized ETPs that contain a strained disulfide bridge across the piperazinedione ring (Chart 1). Sporidesmin and other ETPs exhibit a variety of biological activities, including antibacterial, antiviral, immunosuppressive and antineoplastic actions (12,13). The mode of action of the ETP compounds is unknown but multiple effects have been reported including altered calcium flux (14), interference with NFκB action (15), inhibition of farnesyl and geranylgeranyl transferases (16) and formation of mixed disulfides between the ETP moiety and cysteine residues on vital proteins, as reported for creatine kinase (17).…”

mentioning

confidence: 99%

Selective Inactivation of Glutaredoxin by Sporidesmin and Other Epidithiopiperazinediones^,

et al. 2006

View full text Add to dashboard Cite

Glutaredoxin (thioltransferase) is a thiol-disulfide oxidoreductase that displays efficient and specific catalysis of protein-SSG deglutathionylation and is thereby implicated in homeostatic regulation of the thiol-disulfide status of cellular proteins. Sporidesmin is an epidithiopiperazine-2,5-dione (ETP) fungal toxin that disrupts cellular functions likely via oxidative alteration of cysteine residues on key proteins. In the current study sporidesmin inactivated human glutaredoxin in a time-and concentration-dependent manner. Under comparable conditions other thiol-disulfide oxidoreductase enzymes, glutathione reductase, thioredoxin, and thioredoxin reductase, were unaffected by sporidesmin. Inactivation of glutaredoxin required the reduced (dithiol) form of the enzyme, the oxidized (intramolecular disulfide) form of sporidesmin, and molecular oxygen. The inactivated glutaredoxin could be reactivated by dithiothreitol only in the presence of urea, followed by removal of the denaturant, indicating that inactivation of the enzyme involves a conformationally inaccessible disulfide bond(s). Various cysteine-to-serine mutants of glutaredoxin were resistant to inactivation by sporidesmin, suggesting that the inactivation reaction specifically involves at least two of the five cysteine residues in human glutaredoxin. The relative ability of various epidithiopiperazine-2,5-diones to inactivate glutaredoxin indicated that at least one phenyl substituent was required in addition to the epidithiodioxopiperazine moiety for inhibitory activity. Mass spectrometry of the modified protein is consistent with formation of intermolecular disulfides, containing one adducted toxin per glutaredoxin but with elimination of two sulfur atoms from the detected product. We suggest that the initial reaction is between the toxin sulfurs and cysteine 22 in the glutaredoxin active site. This study implicates selective modification of sulfhydryls of target proteins in some of the cytotoxic effects of the ETP fungal toxins and their synthetic analogs. Keywordsgliotoxin; glutaredoxin; mixed disulfides; sporidesmin; thioltransferase Glutaredoxin (GRx, also known as thioltransferase) is a member of the thiol-disulfide oxidoreductase enzyme family, which also includes thioredoxin and their corresponding reductase enzymes GSSG reductase and thioredoxin reductase, respectively. Mammalian NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2011 October 24. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGRx1 is a 12 kDa cytosolic protein that has been characterized in vitro as a specific catalyst for the reduction of protein-glutathionyl mixed disulfides (protein-SSG) (1-6). The reaction catalyzed by GRx1 is also selective for GSH as the reducing substrate (4). This thioldisulfide interchange reaction is likely crucial for maintaining intracellular thiol status (2-7) under a variety of physiological and pathophysiological processes like aging, cardiovascular and neurodegenerative di...

show abstract

Fungal epipolythiodioxopiperazine toxins have therapeutic potential and roles in disease

Cited by 33 publications

References 20 publications

Antimicrobial constituents of Hypocrea virens, an endophyte of the mangrove-associate plant Premna serratifolia L.

Antimicrobial constituents of Hypocrea virens, an endophyte of the mangrove-associate plant Premna serratifolia L.

Liver Enzyme Changes in a Guinea-Pig Model of Facial Eczema (Sporidesmiotoxicosis)

Selective Inactivation of Glutaredoxin by Sporidesmin and Other Epidithiopiperazinediones^,

Contact Info

Product

Resources

About

Fungal epipolythiodioxopiperazine toxins have therapeutic potential and roles in disease

Cited by 33 publications

References 20 publications

Antimicrobial constituents of Hypocrea virens, an endophyte of the mangrove-associate plant Premna serratifolia L.

Antimicrobial constituents of Hypocrea virens, an endophyte of the mangrove-associate plant Premna serratifolia L.

Liver Enzyme Changes in a Guinea-Pig Model of Facial Eczema (Sporidesmiotoxicosis)

Selective Inactivation of Glutaredoxin by Sporidesmin and Other Epidithiopiperazinediones,

Contact Info

Product

Resources

About

Selective Inactivation of Glutaredoxin by Sporidesmin and Other Epidithiopiperazinediones^,