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11 pages, 1525 KiB

Open AccessArticle

Activation of a Silent Polyketide Synthase SlPKS4 Encoding the C₇-Methylated Isocoumarin in a Marine-Derived Fungus Simplicillium lamellicola HDN13-430

by Jing Yu, Xiaolin Liu, Chuanteng Ma, Chen Li, Yuhan Zhang, Qian Che, Guojian Zhang, Tianjiao Zhu and Dehai Li

Mar. Drugs 2023, 21(9), 490; https://doi.org/10.3390/md21090490 - 13 Sep 2023

Viewed by 1285

Abstract

Coumarins, isocoumarins and their derivatives are polyketides abundant in fungal metabolites. Although they were first discovered over 50 years ago, the biosynthetic process is still not entirely understood. Herein, we report the activation of a silent nonreducing polyketide synthase that encodes a C [...] Read more.

Coumarins, isocoumarins and their derivatives are polyketides abundant in fungal metabolites. Although they were first discovered over 50 years ago, the biosynthetic process is still not entirely understood. Herein, we report the activation of a silent nonreducing polyketide synthase that encodes a C₇-methylated isocoumarin, similanpyrone B (1), in a marine-derived fungus Simplicillium lamellicola HDN13-430 by heterologous expression. Feeding studies revealed the host enzymes can change 1 into its hydroxylated derivatives pestapyrone A (2). Compounds 1 and 2 showed moderate radical scavenging activities with ED₅₀ values of 67.4 µM and 104.2 µM. Our discovery fills the gap in the enzymatic elucidation of naturally occurring C₇-methylated isocoumarin derivatives. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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17 pages, 5543 KiB

Open AccessEditor’s ChoiceArticle

Talarolides Revisited: Cyclic Heptapeptides from an Australian Marine Tunicate-Associated Fungus, Talaromyces sp. CMB-TU011

by Angela A. Salim, Waleed M. Hussein, Pradeep Dewapriya, Huy N. Hoang, Yahao Zhou, Kaumadi Samarasekera, Zeinab G. Khalil, David P. Fairlie and Robert J. Capon

Mar. Drugs 2023, 21(9), 487; https://doi.org/10.3390/md21090487 - 11 Sep 2023

Cited by 1 | Viewed by 2605

Abstract

Application of a miniaturized 24-well plate system for cultivation profiling (MATRIX) permitted optimization of the cultivation conditions for the marine-derived fungus Talaromyces sp. CMB-TU011, facilitating access to the rare cycloheptapeptide talarolide A (1) along with three new analogues, B–D (2 [...] Read more.

Application of a miniaturized 24-well plate system for cultivation profiling (MATRIX) permitted optimization of the cultivation conditions for the marine-derived fungus Talaromyces sp. CMB-TU011, facilitating access to the rare cycloheptapeptide talarolide A (1) along with three new analogues, B–D (2–4). Detailed spectroscopic analysis supported by Marfey’s analysis methodology was refined to resolve N-Me-l-Ala from N-Me-d-Ala, l-allo-Ile from l-Ile and l-Leu, and partial and total syntheses of 2, and permitted unambiguous assignment of structures for 1 (revised) and 2–4. Consideration of diagnostic ROESY correlations for the hydroxamates 1 and 3–4, and a calculated solution structure for 1, revealed how cross-ring H-bonding to the hydroxamate moiety influences (defines/stabilizes) the cyclic peptide conformation. Such knowledge draws attention to the prospect that hydroxamates may be used as molecular bridges to access new cyclic peptide conformations, offering the prospect of new biological properties, including enhanced oral bioavailability. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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13 pages, 1779 KiB

Open AccessArticle

Cytosporin Derivatives from Arctic-Derived Fungus Eutypella sp. D-1 via the OSMAC Approach

by Hao-Bing Yu, Zhe Ning, Bo Hu, Yu-Ping Zhu, Xiao-Ling Lu, Ying He, Bing-Hua Jiao and Xiao-Yu Liu

Mar. Drugs 2023, 21(7), 382; https://doi.org/10.3390/md21070382 - 28 Jun 2023

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Abstract

A chemical investigation of the Arctic-derived fungus Eutypella sp. D-1 based on the OSMAC (one strain many compounds) approach resulted in the isolation of five cytosporin polyketides (compounds 1–3 and 11–12) from rice medium and eight cytosporins (compounds [...] Read more.

A chemical investigation of the Arctic-derived fungus Eutypella sp. D-1 based on the OSMAC (one strain many compounds) approach resulted in the isolation of five cytosporin polyketides (compounds 1–3 and 11–12) from rice medium and eight cytosporins (compounds 2 and 4–11) from solid defined medium. The structures of the seven new compounds, eutypelleudesmane A (1), cytosporin Y (2), cytosporin Z (3), cytosporin Y₁ (4), cytosporin Y₂ (5), cytosporin Y₃ (6), and cytosporin E₁ (7), were elucidated by analyzing their detailed spectroscopic data. Structurally, cytosporin Y₁ (4) may be a key intermediate in the biosynthesis of the isolated cytosporins, rather than an end product. Compound 1 contained a unique skeleton formed by the ester linkage of two moieties, cytosporin F (12) and the eudesmane-type sesquiterpene dihydroalanto glycol. Additionally, the occurrence of cyclic carbonate moieties in compounds 6 and 7 was found to be rare in nature. The antibacterial, immunosuppressive, and cytotoxic activities of all compounds derived from Eutypella sp. D-1 were evaluated. Unfortunately, only compounds 3, 6, 8, and 10–11 displayed immunosuppressive activity, with inhibitory rates of 62.9%, 59.5%, 67.8%, 55.8%, and 68.7%, respectively, at a concentration of 5 μg/mL. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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28 pages, 8481 KiB

Open AccessArticle

Chemomodulatory Effect of the Marine-Derived Metabolite “Terrein” on the Anticancer Properties of Gemcitabine in Colorectal Cancer Cells

by Reham Khaled Abuhijjleh, Dalia Yousef Al Saeedy, Naglaa S. Ashmawy, Ahmed E. Gouda, Sameh S. Elhady and Ahmed Mohamed Al-Abd

Mar. Drugs 2023, 21(5), 271; https://doi.org/10.3390/md21050271 - 26 Apr 2023

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Abstract

Background: Terrein (Terr) is a bioactive marine secondary metabolite that possesses antiproliferative/cytotoxic properties by interrupting various molecular pathways. Gemcitabine (GCB) is an anticancer drug used to treat several types of tumors such as colorectal cancer; however, it suffers from tumor cell resistance, and [...] Read more.

Background: Terrein (Terr) is a bioactive marine secondary metabolite that possesses antiproliferative/cytotoxic properties by interrupting various molecular pathways. Gemcitabine (GCB) is an anticancer drug used to treat several types of tumors such as colorectal cancer; however, it suffers from tumor cell resistance, and therefore, treatment failure. Methods: The potential anticancer properties of terrein, its antiproliferative effects, and its chemomodulatory effects on GCB were assessed against various colorectal cancer cell lines (HCT-116, HT-29, and SW620) under normoxic and hypoxic (pO₂ ≤ 1%) conditions. Further analysis via flow cytometry was carried out in addition to quantitative gene expression and ¹HNMR metabolomic analysis. Results: In normoxia, the effect of the combination treatment (GCB + Terr) was synergistic in HCT-116 and SW620 cell lines. In HT-29, the effect was antagonistic when the cells were treated with (GCB + Terr) under both normoxic and hypoxic conditions. The combination treatment was found to induce apoptosis in HCT-116 and SW620. Metabolomic analysis revealed that the change in oxygen levels significantly affected extracellular amino acid metabolite profiling. Conclusions: Terrein influenced GCB’s anti-colorectal cancer properties which are reflected in different aspects such as cytotoxicity, cell cycle progression, apoptosis, autophagy, and intra-tumoral metabolism under normoxic and hypoxic conditions. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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16 pages, 1964 KiB

Open AccessArticle

Unusual Tetrahydropyridoindole-Containing Tetrapeptides with Human Nicotinic Acetylcholine Receptors Targeting Activity Discovered from Antarctica-Derived Psychrophilic Pseudogymnoascus sp. HDN17-933

by Xuewen Hou, Changlong Li, Runfang Zhang, Yinping Li, Huadong Li, Yundong Zhang, Han-Shen Tae, Rilei Yu, Qian Che, Tianjiao Zhu, Dehai Li and Guojian Zhang

Mar. Drugs 2022, 20(10), 593; https://doi.org/10.3390/md20100593 - 22 Sep 2022

Cited by 2 | Viewed by 1433

Abstract

Chemical investigation of the psychrophilic fungus Pseudogymnoascus sp. HDN17-933 derived from Antarctica led to the discovery of six new tetrapeptides psegymamides A–F (1–6), whose planar structures were elucidated by extensive NMR and MS spectrometric analyses. Structurally, psegymamides D–F ( [...] Read more.

Chemical investigation of the psychrophilic fungus Pseudogymnoascus sp. HDN17-933 derived from Antarctica led to the discovery of six new tetrapeptides psegymamides A–F (1–6), whose planar structures were elucidated by extensive NMR and MS spectrometric analyses. Structurally, psegymamides D–F (4–6) possess unique backbones bearing a tetrahydropyridoindoles unit, which make them the first examples discovered in naturally occurring peptides. The absolute configurations of structures were unambiguously determined using solid-phase total synthesis assisted by Marfey’s method, and all compounds were evaluated for their inhibition of human (h) nicotinic acetylcholine receptor subtypes. Compound 2 showed significant inhibitory activity. A preliminary structure–activity relationship investigation revealed that the tryptophan residue and the C-terminal with methoxy group were important to the inhibitory activity. Further, the high binding affinity of compound 2 to hα4β2 was explained by molecular docking studies. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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13 pages, 2612 KiB

Open AccessArticle

New Polyketides from Mangrove Endophytic Fungus Penicillium sp. BJR-P2 and Their Anti-Inflammatory Activity

by Chen Chen, Geting Ye, Jing Tang, Jialin Li, Wenbin Liu, Li Wu and Yuhua Long

Mar. Drugs 2022, 20(9), 583; https://doi.org/10.3390/md20090583 - 18 Sep 2022

Cited by 5 | Viewed by 2144

Abstract

Four new polyketide compounds, including two new unique isocoumarins penicillol A (1) and penicillol B (2) featuring with spiroketal rings, two new citreoviridin derivatives citreoviridin H (3) and citreoviridin I (4), along with four known [...] Read more.

Four new polyketide compounds, including two new unique isocoumarins penicillol A (1) and penicillol B (2) featuring with spiroketal rings, two new citreoviridin derivatives citreoviridin H (3) and citreoviridin I (4), along with four known analogues were isolated from the mangrove endophytic fungus Penicillium sp. BJR-P2. Their structures were elucidated by extensive spectroscopic methods. The absolute configurations of compounds 1–4 based on electronic circular dichroism (ECD) calculations, DP4+ analysis, and single-crystal X-ray diffraction are presented. All the new compounds were evaluated for anti-inflammatory activity. An anti-inflammatory assay indicated that compound 2 inhibited lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells, with half-maximal inhibitory concentration (IC₅₀) values of 12 μM, being more potent than the positive control, indomethacin (IC₅₀ = 35.8 ± 5.7 μM). Docking study showed that compound 2 was perfectly docking into the active site of murine inducible nitric oxide oxygenase (iNOS) via forming multiple typical hydrogen bonds. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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10 pages, 1524 KiB

Open AccessArticle

Hemiacetalmeroterpenoids A–C and Astellolide Q with Antimicrobial Activity from the Marine-Derived Fungus Penicillium sp. N-5

by Tao Chen, Wencong Yang, Taobo Li, Yihao Yin, Yufeng Liu, Bo Wang and Zhigang She

Mar. Drugs 2022, 20(8), 514; https://doi.org/10.3390/md20080514 - 13 Aug 2022

Cited by 6 | Viewed by 1680

Abstract

Four new compounds including three andrastin-type meroterpenoids hemiacetalmeroterpenoids A-C (1–3), and a drimane sesquiterpenoid astellolide Q (15), together with eleven known compounds (4–14) were isolated from the cultures of the marine-derived fungus Penicillium [...] Read more.

Four new compounds including three andrastin-type meroterpenoids hemiacetalmeroterpenoids A-C (1–3), and a drimane sesquiterpenoid astellolide Q (15), together with eleven known compounds (4–14) were isolated from the cultures of the marine-derived fungus Penicillium sp. N-5, while compound 14 was first isolated from a natural source. The structures of the new compounds were determined by analysis of detailed spectroscopic data, and the absolute configurations were further decided by a comparison of the experimental and calculated ECD spectra. Hemiacetalmeroterpenoid A (1) possesses a unique and highly congested 6,6,6,6,5,5-hexa-cyclic skeleton. Moreover, the absolute configuration of compound 14 was also reported for the first time. Compounds 1, 5 and 10 exhibited significant antimicrobial activities against Penicillium italicum and Colletrichum gloeosporioides with MIC values ranging from 1.56 to 6.25 μg/mL. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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Review

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17 pages, 3419 KiB

Open AccessReview

Marine Aspergillus: A Treasure Trove of Antimicrobial Compounds

by Honghua Li, Yanqi Fu and Fuhang Song

Mar. Drugs 2023, 21(5), 277; https://doi.org/10.3390/md21050277 - 28 Apr 2023

Cited by 3 | Viewed by 1795

Abstract

Secondary metabolites from marine organisms are diverse in structure and function. Marine Aspergillus is an important source of bioactive natural products. We reviewed the structures and antimicrobial activities of compounds isolated from different marine Aspergillus over the past two years (January 2021–March 2023). [...] Read more.

Secondary metabolites from marine organisms are diverse in structure and function. Marine Aspergillus is an important source of bioactive natural products. We reviewed the structures and antimicrobial activities of compounds isolated from different marine Aspergillus over the past two years (January 2021–March 2023). Ninety-eight compounds derived from Aspergillus species were described. The chemical diversity and antimicrobial activities of these metabolites will provide a large number of promising lead compounds for the development of antimicrobial agents. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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32 pages, 4512 KiB

Open AccessReview

Fungal Bergamotane Sesquiterpenoids—Potential Metabolites: Sources, Bioactivities, and Biosynthesis

by Maan T. Khayat, Khadijah A. Mohammad, Abdelsattar M. Omar, Gamal A. Mohamed and Sabrin R. M. Ibrahim

Mar. Drugs 2022, 20(12), 771; https://doi.org/10.3390/md20120771 - 08 Dec 2022

Cited by 3 | Viewed by 1401

Abstract

The marine environment represents the largest ecosystem on the Earth’s surface. Marine-derived fungi are of remarkable importance as they are a promising pool of diverse classes of bioactive metabolites. Bergamotane sesquiterpenoids are an uncommon class of terpenoids. They possess diverse biological properties, such [...] Read more.

The marine environment represents the largest ecosystem on the Earth’s surface. Marine-derived fungi are of remarkable importance as they are a promising pool of diverse classes of bioactive metabolites. Bergamotane sesquiterpenoids are an uncommon class of terpenoids. They possess diverse biological properties, such as plant growth regulation, phototoxic, antimicrobial, anti-HIV, cytotoxic, pancreatic lipase inhibition, antidiabetic, anti-inflammatory, and immunosuppressive traits. The current work compiles the reported bergamotane sesquiterpenoids from fungal sources in the period ranging from 1958 to June 2022. A total of 97 compounds from various fungal species were included. Among these metabolites, 38 compounds were derived from fungi isolated from different marine sources. Furthermore, the biological activities, structural characterization, and biosynthesis of the compounds are also discussed. The summary in this work provides a detailed overview of the reported knowledge of fungal bergamotane sesquiterpenoids. Moreover, this in-depth and complete review could provide new insights for developing and discovering new valuable pharmaceutical agents from these natural metabolites. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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13 pages, 1232 KiB

Open AccessReview

Application of Gene Knockout and Heterologous Expression Strategy in Fungal Secondary Metabolites Biosynthesis

by Yaodong Ning, Yao Xu, Binghua Jiao and Xiaoling Lu

Mar. Drugs 2022, 20(11), 705; https://doi.org/10.3390/md20110705 - 10 Nov 2022

Cited by 10 | Viewed by 2447

Abstract

The in-depth study of fungal secondary metabolites (SMs) over the past few years has led to the discovery of a vast number of novel fungal SMs, some of which possess good biological activity. However, because of the limitations of the traditional natural product [...] Read more.

The in-depth study of fungal secondary metabolites (SMs) over the past few years has led to the discovery of a vast number of novel fungal SMs, some of which possess good biological activity. However, because of the limitations of the traditional natural product mining methods, the discovery of new SMs has become increasingly difficult. In recent years, with the rapid development of gene sequencing technology and bioinformatics, new breakthroughs have been made in the study of fungal SMs, and more fungal biosynthetic gene clusters of SMs have been discovered, which shows that the fungi still have a considerable potential to produce SMs. How to study these gene clusters to obtain a large number of unknown SMs has been a research hotspot. With the continuous breakthrough of molecular biology technology, gene manipulation has reached a mature stage. Methods such as gene knockout and heterologous expression techniques have been widely used in the study of fungal SM biosynthesis and have achieved good effects. In this review, the representative studies on the biosynthesis of fungal SMs by gene knockout and heterologous expression under the fungal genome mining in the last three years were summarized. The techniques and methods used in these studies were also briefly discussed. In addition, the prospect of synthetic biology in the future under this research background was proposed. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products)

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