Gliotoxin, The Antibiotic Principle of Gliocladium fimbriatum. I. Production, Physical and Biological Properties<sup>1</sup>

Johnson, John R.; Bruce, William F.; Dutcher, James D.

doi:10.1021/ja01250a051

Cited by 162 publications

(55 citation statements)

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“…Our observation that S. cerevisiae Dgsh1, severely deficient in GSH (Lee et al, 2001), exhibits greater resistance to gliotoxin than wild-type -and that complementation with GSH1 restores wild-type levels of gliotoxin sensitivity -further underpins our proposal that intracellular GSH levels play an important role in mediating gliotoxin cytotoxicity in fungi as has been noted in animals cells by Bernardo et al (2003). Gliotoxin was originally investigated as an antifungal antibiotic (Johnson et al, 1943). Later, Losada et al (2009) investigated the presence of antifungal agents produced by Aspergillus spp and detected gliotoxin in fungal co-culture extracts by LC-MS analysis.…”

Section: Discussionsupporting

confidence: 62%

Gliotoxin effects on fungal growth: Mechanisms and exploitation

Carberry

Molloy

Hammel

et al. 2012

Fungal Genetics and Biology

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a b s t r a c tAlthough initially investigated for its antifungal properties, little is actually known about the effect of gliotoxin on Aspergillus fumigatus and other fungi. We have observed that exposure of A. fumigatus to exogenous gliotoxin (14 lg/ml), under gliotoxin-limited growth conditions, results in significant alteration of the expression of 27 proteins (up-and down-regulated >1.9-fold; p < 0.05) including de novo expression of Cu, Zn superoxide dismutase, up-regulated allergen Asp f3 expression and down-regulated catalase and a peroxiredoxin levels. Significantly elevated glutathione GSH levels (p < 0.05), along with concomitant resistance to diamide, were evident in A. fumigatus DgliT, lacking gliotoxin oxidoreductase, a gliotoxin self-protection gene. Saccharomyces cerevisiae deletents (Dsod1 and Dyap1) were hypersensitive to exogenous gliotoxin, while Dgsh1 was resistant. Significant gliotoxin-mediated (5 lg/ml) growth inhibition (p < 0.001) of Aspergillus nidulans, Aspergillus terreus, Aspergillus niger, Cochliobolus heterostrophus and Neurospora crassa was also observed. Growth of Aspergillus flavus, Fusarium graminearum and Aspergillus oryzae was significantly inhibited (p < 0.001) at gliotoxin (10 lg/ml), indicating differential gliotoxin sensitivity amongst fungi. Re-introduction of gliT into A. fumigatus DgliT, at a different locus (ctsD; AFUA_4G07040, an aspartic protease), with selection on gliotoxin, facilitated deletion of ctsD without use of additional antibiotic selection markers. Absence of ctsD expression was accompanied by restoration of gliT expression, and resistance to gliotoxin. Thus, we propose gliT/gliotoxin as a useful selection marker system for fungal transformation. Finally, we suggest incorporation of gliotoxin sensitivity assays into all future fungal functional genomic studies.

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Section: Discussionsupporting

confidence: 62%

Gliotoxin effects on fungal growth: Mechanisms and exploitation

Carberry

Molloy

Hammel

et al. 2012

Fungal Genetics and Biology

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“…liotoxin was discovered in 1936, and its structure was elucidated in 1943 (19,38). Much initial interest in the molecule was directed toward exploiting its antifungal activities; however, after observations that gliotoxin exhibited growth-inhibitory effects against animal cells, it was posited as a putative anti-cancer or organ transplant rejection agent, and a large number of subsequent studies investigated the mechanism of action of gliotoxin against mammalian cell types (3,24,37).…”

mentioning

confidence: 99%

The Aspergillus fumigatus Protein GliK Protects against Oxidative Stress and Is Essential for Gliotoxin Biosynthesis

et al. 2012

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The function of a number of genes in the gliotoxin biosynthetic cluster (gli) in Aspergillus fumigatus remains unknown. Here, we demonstrate that gliK deletion from two strains of A. fumigatus completely abolished gliotoxin biosynthesis. Furthermore, exogenous H 2 O 2 (1 mM), but not gliotoxin, significantly induced A. fumigatus gliK expression (P ‫؍‬ 0.0101). While both mutants exhibited significant sensitivity to both exogenous gliotoxin (P < 0.001) and H 2 O 2 (P < 0.01), unexpectedly, exogenous gliotoxin relieved H 2 O 2 -induced growth inhibition in a dose-dependent manner (0 to 10 g/ml). Gliotoxin-containing organic extracts derived from A. fumigatus ATCC 26933 significantly inhibited (P < 0.05) the growth of the ⌬gliK 26933 deletion mutant. The A. fumigatus ⌬gliK 26933 mutant secreted metabolites, devoid of disulfide linkages or free thiols, that were detectable by reverse-phase high-performance liquid chromatography and liquid chromatography-mass spectrometry with m/z 394 to 396. These metabolites (m/z 394 to 396) were present at significantly higher levels in the culture supernatants of the A. fumigatus ⌬gliK 26933 mutant than in those of the wild type (P ‫؍‬ 0.0024 [fold difference, 24] and P ‫؍‬ 0.0003 [fold difference, 9.6], respectively) and were absent from A. fumigatus ⌬gliG. Significantly elevated levels of ergothioneine were present in aqueous mycelial extracts of the A. fumigatus ⌬gliK 26933 mutant compared to the wild type (P < 0.001). Determination of the gliotoxin uptake rate revealed a significant difference (P ‫؍‬ 0.0045) between that of A. fumigatus ATCC 46645 (9.3 pg/mg mycelium/min) and the ⌬gliK 46645 mutant (31.4 pg/mg mycelium/min), strongly suggesting that gliK absence and the presence of elevated ergothioneine levels impede exogenously added gliotoxin efflux. Our results confirm a role for gliK in gliotoxin biosynthesis and reveal new insights into gliotoxin functionality in A. fumigatus. Gliotoxin was discovered in 1936, and its structure was elucidated in 1943 (19, 38). Much initial interest in the molecule was directed toward exploiting its antifungal activities; however, after observations that gliotoxin exhibited growth-inhibitory effects against animal cells, it was posited as a putative anti-cancer or organ transplant rejection agent, and a large number of subsequent studies investigated the mechanism of action of gliotoxin against mammalian cell types (3, 24, 37).Until recently, the mechanism of gliotoxin biosynthesis had proven to be especially refractory to analysis, despite multiple studies between 1960 and 1985 involving radiolabeled precursor feeding and analysis of proteins produced during gliotoxin biosynthesis (2, 18). Since the discovery of the gliotoxin gene cluster gli (14), now known to contain 13 genes, the function of a number of cluster genes has been established by a combination of targeted gene deletion and phenotypic and biochemical analyses (4, 10, 11, 13, 22, 31-33, 34, 36). gliZ [a Zn(II) 2 -Cys(6) binuclear cluster domain transcription factor] deletio...

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“…In addition to potent antibiotic properties, gliotoxin was acutely toxic to rabbits (LD50 -45 mg/kg), mice (LD50 -50mg/kg), and rats (LD5o -50-65mg/kg) (88); at sublethal doses the animals had kidney lesions. A comprehensive review of the biosynthesis of epipolythiodioxopiperazines was presented by Taylor (87 …”

Section: Colementioning

confidence: 99%

Aspergillus Toxins Other Than Aflatoxin

Cole

1976

Advances in Chemistry

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Available physical, chemical, and biological data are presented for all known Aspergillus mycotoxins other than the aflatoxins with emphasis on the chemistry of those that are of major interest. Included in this latter category are the ochratoxins, the sterigmatocystins, and the aspergillic acid group. Other Aspergillus mycotoxins presented in less detail are kojic acid, austamide, ascladiol, terreic acid, viriditoxin, cytochalasin E, maltoryzine, 3-nitropropanoic acid, oxalic acid, helvolic acid, gliotoxin, fumigatin, fumagillin, terrein, spinulosin, and butenolide.

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Gliotoxin, The Antibiotic Principle of Gliocladium fimbriatum. I. Production, Physical and Biological Properties¹

Cited by 162 publications

References 0 publications

Gliotoxin effects on fungal growth: Mechanisms and exploitation

Gliotoxin effects on fungal growth: Mechanisms and exploitation

The Aspergillus fumigatus Protein GliK Protects against Oxidative Stress and Is Essential for Gliotoxin Biosynthesis

Aspergillus Toxins Other Than Aflatoxin

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Gliotoxin, The Antibiotic Principle of Gliocladium fimbriatum. I. Production, Physical and Biological Properties1

Cited by 162 publications

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Gliotoxin effects on fungal growth: Mechanisms and exploitation

Gliotoxin effects on fungal growth: Mechanisms and exploitation

The Aspergillus fumigatus Protein GliK Protects against Oxidative Stress and Is Essential for Gliotoxin Biosynthesis

Aspergillus Toxins Other Than Aflatoxin

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Gliotoxin, The Antibiotic Principle of Gliocladium fimbriatum. I. Production, Physical and Biological Properties¹