Ophiobolins from the Mangrove Fungus <i>Aspergillus ustus</i>

Zhu, Tonghan; Lu, Zhenyu; Fan, Jie; Wang, Liping; Zhu, Guoliang; Wang, Yi; Li, Xia; Hong, Kui; Piyachaturawat, Pawinee; Chairoungdua, Arthit; Zhu, Weiming

doi:10.1021/acs.jnatprod.7b00335

Cited by 48 publications

(53 citation statements)

References 38 publications

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“…The major molecular cluster in the co-culture of Acremonium sp. with P. syringae was however annotated as ophiobolin type sesterterpenes with reported antimicrobial and phytotoxic activities ( Sohsomboon et al, 2018 ; Zhu et al, 2018 ). The ecological role of ophiobolins still remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Molecular Networking-Based Metabolome and Bioactivity Analyses of Marine-Adapted Fungi Co-cultivated With Phytopathogens

et al. 2018

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Fungi represent a rich source of bioactive metabolites and some are marketed as alternatives to synthetic agrochemicals against plant pathogens. However, the culturability of fungal strains in artificial laboratory conditions is still limited and the standard mono-cultures do not reflect their full spectrum chemical diversity. Phytopathogenic fungi and bacteria have successfully been used in the activation of cryptic biosynthetic pathways to promote the production of new secondary metabolites in co-culture experiments. The aim of this study was to map the fungal diversity of Windebyer Noor, a brackish lake connected to Baltic Sea (Germany), to induce the chemical space of the isolated marine-adapted fungi by co-culturing with phytopathogens, and to assess their inhibitory potential against six commercially important phytopathogens. Out of 123 marine-adapted fungal isolates obtained, 21 were selected based on their phylogenetic and metabolite diversity. They were challenged with two phytopathogenic bacteria (Pseudomonas syringae and Ralstonia solanacearum) and two phytopathogenic fungi (Magnaporthe oryzae and Botrytis cinerea) on solid agar. An in-depth untargeted metabolomics approach incorporating UPLC–QToF–HRMS/MS-based molecular networking (MN), in silico MS/MS databases, and manual dereplication was employed for comparative analysis of the extracts belonging to nine most bioactive co-cultures and their respective mono-cultures. The phytopathogens triggered interspecies chemical communications with marine-adapted fungi, leading to the production of new compounds and enhanced expression of known metabolites in co-cultures. MN successfully generated a detailed map of the chemical inventory of both mono- and co-cultures. We annotated overall 18 molecular clusters (belonging to terpenes, alkaloids, peptides, and polyketides), 9 of which were exclusively produced in co-cultures. Several clusters contained compounds, which could not be annotated to any known compounds, suggesting that they are putatively new metabolites. Direct antagonistic effects of the marine-adapted fungi on the phytopathogens were observed and anti-phytopathogenic activity was demonstrated.The untargeted metabolomics approach combined with bioactivity testing allowed prioritization of two co-cultures for purification and characterization of marine fungal metabolites with crop-protective activity. To our knowledge, this is the first study employing plant pathogens to challenge marine-adapted fungi.

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Section: Discussionmentioning

confidence: 99%

Molecular Networking-Based Metabolome and Bioactivity Analyses of Marine-Adapted Fungi Co-cultivated With Phytopathogens

et al. 2018

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“…About 500 µL blood samples were collected at 0. 5,1,2,3,4,5,6,8,10,12,16,20,24,30 and 36 h into heparinized tubes after the intragastric administration of MHO7. All blood samples were immediately centrifuged at 8000 g for 5 min and the resulting plasma was transferred and then processed as described in sample preparation for the analysis by LC-MS/MS.…”

Section: Pharmacokinetic Studies Assaymentioning

confidence: 99%

“…Ophiobolins (Ophs) are a very rare group of sesterterpenoids that bear a unique 5-8-5 tricarbocyclic in structure [5]. At present, 72 Ophs have been reported including 35 Ophs which were produced by marine-derived fungus [5,[7][8][9]. The family shows significant inhibitory effects on the growth of a variety of cancer cells, drug-resistant cells, and cancer stem cells [5].…”

Section: Introductionmentioning

confidence: 99%

Toxicity, Pharmacokinetics, and Gut Microbiome of Oral Administration of Sesterterpene MHO7 Derived from a Marine Fungus

Tian

Deng

et al. 2019

Marine Drugs

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Sesterterpene MHO7 derived from mangrove fungus is a novel estrogen receptor degrader for the treatment of breast cancer. To explore its safety and pharmacokinetics in vivo, Log P/D values, stability in simulated gastric/intestinal (SGF/SIF), toxicity, and pharmacokinetics studies were carried mainly by liquid chromatography technique coupled with tandem mass spectrometry (LC–MS/MS) method in mice, and the effect of MHO7 on mice gut microbiota at different time points was revealed by 16S rRNA sequencing. Log P/D values ranged 0.93–2.48, and the compound in SGF and SIF is stable under the concentration of 5 mM·L−1. The maximum tolerance dose (MTD) of oral administration in mice was 2400 mg·kg−1. The main pharmacokinetics parameters were as following: Cmax of 1.38 μg·mL−1, Tmax of 8 h, a half-life (t1/2) of 6.97 h, an apparent volume of mean residual time (MRT) of 8.76 h, and an area under the curve (AUC) of 10.50 h·μg·mL−1. MHO7 displayed a wide tissue distribution in mice, with most of the compound in liver (3.01 ± 1.53 μg·g−1) at 1 h, then in fat (5.20 ± 3.47 μg·g−1) at 4 h, and followed by reproductive organs with the concentrations of 23.90 ± 11.33 μg·g−1,13.69 ± 10.29 μg·g−1, 1.46 ± 1.23 μg·g−1, and 0.36 ± 0.46 μg·g−1 at 8, 12, 20 and 30 h, respectively. The most influenced genera of gut microbiome belonged to phylum Firmicutes (21 of 28), among which 18 genera originated from the order Clostridiales, class Clostridia, and families of Ruminococcaceae (11 of 18) and Lachnospiraceae (4 of 18). These results provide that MHO7 is suitable for oral administration in the treatment of breast cancer with the target organs of reproductive organs and regulation on Ruminococcaceae and Lachnospiraceae.

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“…To further investigate the biosynthetic capacity of A. ustus , this fungus was cultured in both liquid and on solid media to obtain extracts enriched with ophiobolin derivatives. Eventually, the chromatographic work-up of both extracts yielded seven new and eleven known ophiobolin congeners [ 55 ]. Interestingly, ophiobolins were only produced during static cultivation, but not in the shaking mode.…”

Section: Bioactive Compounds From Mangrove-associated Microorganismentioning

confidence: 99%

“…Compounds 115 – 124 ( Figure 17 ) showed cytotoxicity against the human gemcitabine-resistant G3K (pancreatic cancer) cell line, MCF-7, MD-MBA-231 (triple-negative breast cancer) cells, MCF-7/Adr (adriamycin-resistant human breast cancer) cell line, MCF-10A (nontumorigenic breast epithelial cell line), A549, and HL-60 cells, with IC 50 values in the range from 0.6 to 9.5 μM. Among the tested compounds, 21- epi -ophiobolin O ( 121 ) was found to be the most active analog, with IC 50 values of 0.6 and 0.8 μM toward the A549 and HL-60 cell lines, respectively, thus suggesting that the 2,5-dimethoxyl-2 H ,3 H ,5 H -furan moiety is a key structural feature for cytotoxicity against the tested cell lines [ 55 ]. It should be noted that ophiobolin O ( 122 ) has previously been shown to induce cell apoptosis in human breast cancer MCF-7 cells via activation of mitogen-activated protein kinase (MAPK) signaling pathways [ 56 ].…”

Section: Bioactive Compounds From Mangrove-associated Microorganismentioning

confidence: 99%

Lead Compounds from Mangrove-Associated Microorganisms

2018

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The mangrove ecosystem is considered as an attractive biodiversity hotspot that is intensively studied in the hope of discovering new useful chemical scaffolds, including those with potential medicinal application. In the past two decades, mangrove-derived microorganisms, along with mangrove plants, proved to be rich sources of bioactive secondary metabolites as exemplified by the constant rise in the number of publications, which suggests the great potential of this important ecological niche. The present review summarizes selected examples of bioactive compounds either from mangrove endophytes or from soil-derived mangrove fungi and bacteria, covering the literature from 2014 to March 2018. Accordingly, 163 natural products are described in this review, possessing a wide range of potent bioactivities, such as cytotoxic, antibacterial, antifungal, α-glucosidase inhibitory, protein tyrosine phosphatase B inhibitory, and antiviral activities, among others.

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Ophiobolins from the Mangrove Fungus Aspergillus ustus

Cited by 48 publications

References 38 publications

Molecular Networking-Based Metabolome and Bioactivity Analyses of Marine-Adapted Fungi Co-cultivated With Phytopathogens

Molecular Networking-Based Metabolome and Bioactivity Analyses of Marine-Adapted Fungi Co-cultivated With Phytopathogens

Toxicity, Pharmacokinetics, and Gut Microbiome of Oral Administration of Sesterterpene MHO7 Derived from a Marine Fungus

Lead Compounds from Mangrove-Associated Microorganisms

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