Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus  Neosartorya pseudofischeri

Liang, Wei; Le, Xiu; Li, Hou-Jin; Yang, Xiangling; Chen, Junxiong; Xu, Jing; Liu, Huanliang; Wang, Laiyou; Wang, Kun-Teng; Hu, Kun-Chao; Yang, Dan; Lan, Wen‐Jian

doi:10.3390/md12115657

Cited by 68 publications

(52 citation statements)

References 37 publications

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“…Indeed, gliotoxin significantly inhibits growth of a range of fungi, 12,46 and previously work has also indicated its potent anti-bacterial activity. 47 It is clear that interference with intracellular DTG levels, via gliotoxin exposure to A. fumigatus DgliT impacts on the fungal proteome, which in turn can be modulated by Zn 2+ presence.…”

Section: +mentioning

confidence: 99%

Systems impact of zinc chelation by the epipolythiodioxopiperazine dithiol gliotoxin inAspergillus fumigatus: a new direction in natural product functionality

et al. 2018

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Significance to metallomicsDithiol gliotoxin is a near-terminal biosynthetic intermediate from the gliotoxin biosynthetic pathway in the human pathogen Aspergillus fumigatus. Chemically reduced gliotoxin, dithiol gliotoxin (DTG), is revealed as a biological zinc chelator, and conversely, zinc can relieve the hitherto cryptic fungal autotoxicity of DTG. There is a systems-wide impact of zinc chelation by DTG on the fungal proteome, and we suggest it is DTG, as opposed to gliotoxin, which chelates zinc from metalloproteins. Since gliotoxin can be sequestered by both fungi and bacteria, our findings infer a new avenue to interfere with, and exploit, cellular zinc homeostasis in microorganisms. IntroductionGliotoxin and holomycin are microbial natural products, which are produced by fungal and bacterial spp., respectively (Fig. 1). [1][2][3] Both are low molecular mass metabolites, and each contains a disulphide bridge formed by the action of oxidoreductases, namely GliT and HlmI, on the respective dithiol precursor (Fig. 1). [4][5][6] Disulphide bridge formation is essential for microbial self-protection against these reactive dithiol intermediates, and is a pre-requisite for the Major Facilitator Superfamily transporter GliA-mediated secretion of gliotoxin by Aspergillus fumigatus. 5-8Both metabolites are also present as bis-thiomethylated forms, and gliotoxin bis-thiomethyltransferase GtmA converts dithiol gliotoxin (DTG) to bis-dethiobis(methylthio)gliotoxin (BmGT) in A. fumigatus, whereas the origin of the cognate activity against dithiol holomycin in Streptomyces clavuligeris is unknown (Fig. 1). 9,10Bernardo et al. have shown that upon uptake by eukaryotic cells,

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Section: +mentioning

confidence: 99%

Systems impact of zinc chelation by the epipolythiodioxopiperazine dithiol gliotoxin inAspergillus fumigatus: a new direction in natural product functionality

et al. 2018

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“…There is evidence to suggest that gliotoxin is a promising anticancer reagent that induces cytotoxic effects on cancer cells (21)(22)(23). Previously, we observed that reduced-exerted the most potent anticancer effects compared to other gliotoxin analogues (14). In this study, we examined the potency of reduced-gliotoxin against CRC cells and the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 93%

“…Reagents details and use. Reduced-gliotoxin was isolated from the secondary metabolites of the marine fungus, Neosartorya pseudofischeri, following the procedure described previously (14). The purity of reduced-gliotoxin was >98% as determined by high-performance liquid chromatography (HPLC).…”

Section: Methodsmentioning

confidence: 99%

“…Marine fungi are an important source of structurally unique and biologically active natural products (12,13). In recent years, research has been conducted on the metabolites of marine fungi and obtained the optimized cultivation parameters with which to isolate and identify a series of novel and/or bioactive metabolites (14)(15)(16)(17). Gliotoxin and its analogues, the diketopiperazines of various fungal species, e.g., Aspergrillus fumigatus, Eurotium chevalieri, Trichoderma virens, Neosartorya pseudofischeri, and some Prenicillium and Acremonium species, are known to be immunosuppressive agents (18) and have also been reported to have anticancer properties (19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

“…Gliotoxin and its analogues, the diketopiperazines of various fungal species, e.g., Aspergrillus fumigatus, Eurotium chevalieri, Trichoderma virens, Neosartorya pseudofischeri, and some Prenicillium and Acremonium species, are known to be immunosuppressive agents (18) and have also been reported to have anticancer properties (19)(20)(21)(22)(23). Furthermore, reduced-gliotoxin has previously been shown to possess the most potent cytotoxic effect compared to other analogues in CRC cells (14). However, the detailed effects and molecular mechanisms responsible for the death of CRC cells induced by reduced-gliotoxin are unclear.…”

Section: Introductionmentioning

confidence: 99%

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Reduced-gliotoxin induces ROS-mediated anoikis in human colorectal cancer cells

et al. 2018

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Reduced-gliotoxin is a small molecule derived from the secondary metabolites of marine fungi; compared to other gliotoxin analogues, it exhibits potent anticancer effects. However, the molecular basis of the death of colorectal cancer (CRC) cells induced by reduced-gliotoxin is unclear. Thus, the aim of this study was to investigate the potency of reduced-gliotoxin against CRC cells and to elucidate the underlying mechanisms. Cell morphology, flow cytometric analysis and western bolt analysis were performed to examine the functions and mechanisms of cell death induced by reduced-gliotoxin. Our findings demonstrated that reduced-gliotoxin triggered rapid cell detachment and induced anoikis in CRC cells. Mechanistically, our data indicated that the anoikis induced by reduced-gliotoxin was associated with the disruption of integrin-associated cell detachment and multiple signaling pathways. Furthermore, reduced-gliotoxin induced the excessive production of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP), resulting in the activation of both endogenous and exogenous apoptotic pathways and eventually, in the apoptosis of CRC cells. The blockage of ROS generation with N-acetylcysteine (NAC) attenuated the anoikis induced by reduced-gliotoxin. Taken together, these results suggest that reduced-gliotoxin may prove to be a potential candidate in the treatment of CRC.

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