Phenylhydrazone Alkaloids from the Deep-Sea Cold Seep Derived Fungus Talaromyces amestolkiae HDN21-0307.

Alkaloids with a phenylhydrazone architecture are rarely found in nature. Four unusual phenylhydrazone alkaloids named talarohydrazones A-D (1-4) were isolated from the deep-sea cold seep derived fungus Talaromyces amestolkiae HDN21-0307 using the one strain-many compounds (OSMAC) approach and MS/MS-based molecular networking (MN) combined with network annotation propagation (NAP) and the unsupervised substructure annotation method MS2LDA. Their structures were elucidated by spectroscopic data analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Talarohydrazone A (1) possessed an unusual skeleton combining 2,4-pyridinedione and phenylhydrazone. Talarohydrazone B (2) represents the first natural phenylhydrazone-bearing azadophilone. Bioactivity evaluation revealed that compound 1 exhibited cytotoxic activity against NCI-H446 cells with an IC50 value of 4.1 µM. In addition, compound 1 displayed weak antibacterial activity toward Staphylococcus aureus with an MIC value of 32 µg/mL.

Polyketide Derivatives from the Mangrove-Derived Fungus Penicillium sp. HDN15-312.

Four new polyketides, namely furantides A-B (1-2), talamin E (3) and arugosinacid A (4), and two known polyketides were obtained from the mangrove-derived fungus Penicillium sp. HDN15-312 using the One Strain Many Compounds (OSMAC) strategy. Their chemical structures, including configurations, were elucidated by detailed analysis of extensive NMR spectra, HRESIMS and ECD. The DPPH radicals scavenging activity of 3, with an IC50 value of 6.79 µM, was better than vitamin C.

Combining the Elicitor Up-Regulated Production of Unusual Linear Diterpene-Derived Variants for an In-Depth Assessment of the Application Value and Risk of the Medicinal and Edible Basidiomycete Schizophyllum commune.

To better assess the practical value and avoid potential risks of the traditionally medicinal and edible basidiomycete Schizophyllum commune, which may arise from undescribed metabolites, a combination of elicitors was introduced for the first time to discover products from cryptic and low-expressed gene clusters under laboratory cultivation. Treating S. commune NJFU21 with the combination of five elicitors led to the upregulated production of a class of unusual linear diterpene-derived variants, including eleven new ones (1-11), along with three known ones (12-14). The structures and stereochemistry were determined by 1D and 2D NMR, HRESIMS, ECD, OR and VCD calculations. Notably, the elongation terminus of all the diterpenes was decorated by an unusual butenedioic acid moiety. Compound 1 was a rare monocyclic diterpene, while 2-6 possessed a tetrahydrofuran moiety. The truncated metabolites 4, 5 and 13 belong to the trinorditerpenes. All the diterpenes displayed approximately 70% scavenging of hydroxyl radicals at 50 µM and null cytotoxic activity at 10 µM. In addition, compound 1 exhibited potent antifungal activity against the plant pathogenic fungi Colletotrichum camelliae, with MIC values of 8 µg/mL. Our findings indicated that this class of diterpenes could provide valuable protectants for cosmetic ingredients and the lead compounds for agricultural fungicide development.

Discovery, Total Synthesis, and Anti-Inflammatory Evaluation of Naturally Occurring Naphthopyrone-Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors.

Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A-C (1-3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17-895, which represent the first naturally occurring naphthopyrone-macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro-inflammatory cytokine IL-1ß release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome.

Microbial Dimerization and Chlorination of Isoflavones by a Takla Makan Desert-Derived Streptomyces sp. HDN154127.

Sixteen new biisoflavones, bisoflavolins A-N (1-16), were discovered from cultures of the Takla Makan desert-derived strain Streptomyces sp. HDN154127. The chemical structures, including axial chirality, were elucidated by NMR, MS, and ECD analyses. Antibacterial activity of dimerized compounds was tested against seven different bacteria. The dimerized compounds showed better activity (MIC from 0.8 to 50.0 µM) than the corresponding monomers (daidzein and genistein, MIC > 50.0 µM). The rare dimeric and chlorinated structures in 1-16 were proved to be biotransformation products obtained from soy isoflavones and sodium chloride, which constituted the culture medium. This is the first report of an actinomycete that promotes both dimerization and chlorination utilizing natural isoflavones as skeletons sources.

Filamentous Fungi-Derived Orsellinic Acid-Sesquiterpene Meroterpenoids: Fungal Sources, Chemical Structures, Bioactivities, and Biosynthesis.

Fungi-derived polyketide-terpenoid hybrids are important meroterpenoid natural products that possess diverse structure scaffolds with a broad spectrum of bioactivities. Herein, we focus on an ever-increasing group of meroterpenoids, orsellinic acid-sesquiterpene hybrids comprised of biosynthetic start unit orsellinic acid coupling to a farnesyl group or/and its modified cyclic products. The review entails the search of China National Knowledge Infrastructure (CNKI), Web of Science, Science Direct, Google Scholar, and PubMed databases up to June 2022. The key terms include "orsellinic acid", "sesquiterpene", "ascochlorin", "ascofuranone", and "Ascochyta viciae", which are combined with the structures of "ascochlorin" and "ascofuranone" drawn by the Reaxys and Scifinder databases. In our search, these orsellinic acid-sesquiterpene hybrids are mainly produced by filamentous fungi. Ascochlorin was the first compound reported in 1968 and isolated from filamentous fungus Ascochyta viciae (synonym: Acremonium egyptiacum; Acremonium sclerotigenum); to date, 71 molecules are discovered from various filamentous fungi inhabiting in a variety of ecological niches. As typical representatives of the hybrid molecules, the biosynthetic pathway of ascofuranone and ascochlorin are discussed. The group of meroterpenoid hybrids exhibits a broad arrange of bioactivities, as highlighted by targeting hDHODH (human dihydroorotate dehydrogenase) inhibition, antitrypanosomal, and antimicrobial activities. This review summarizes the findings related to the structures, fungal sources, bioactivities, and their biosynthesis from 1968 to June 2022.

Overexpression of Global Regulator SCrp Leads to the Discovery of New Angucyclines in Streptomyces sp. XS-16.

Six angucyclines including three unreported compounds (1-3) were isolated from Streptomyces sp. XS-16 by overexpressing the native global regulator of SCrp (cyclic AMP receptor). The structures were characterized based on nuclear magnetic resonance (NMR) and spectrometry analysis and assisted by electronic circular dichroism (ECD) calculations. All compounds were tested for their antitumor and antimicrobial activities, and compound 1 showed different inhibitory activities against various tumor cell lines with IC50 values ranging from 0.32 to 5.33 µM.

Saliniquinone Derivatives, Saliniquinones G-I and Heraclemycin E, from the Marine Animal-Derived Nocardiopsis aegyptia HDN19-252.

Four new anthraquinone derivatives, namely saliniquinones G-I (1-3) and heraclemycin E (4), were obtained from the Antarctic marine-derived actinomycete Nocardiopsis aegyptia HDN19-252, guided by the Global Natural Products Social (GNPS) molecular networking platform. Their structures, including absolute configurations, were elucidated by extensive NMR, MS, and ECD analyses. Compounds 1 and 2 showed promising inhibitory activity against six tested bacterial strains, including methicillin-resistant coagulase-negative staphylococci (MRCNS), with MIC values ranging from 3.1 to 12.5 µM.

New Glutamine-Containing Azaphilone Alkaloids from Deep-Sea-Derived Fungus Chaetomium globosum HDN151398.

Three new azaphilone alkaloids containing glutamine residues, namely N-glutarylchaetoviridins A-C (1-3), together with two related compounds (4 and 5) were isolated from the extract of Chaetomium globosum HDN151398, a fungus isolated from a deep-sea sediment sample collected in South China Sea. Their structures were elucidated on the basis of extensive 1D and 2D NMR as well as HRESIMS spectroscopic data and chemical analysis. N-glutarylchaetoviridins A-C (1-3) represent the first class of chaetoviridins characterized by embedded glutamate residues. Amino acids incubation experiments produced five azaphilone laden different amino acids residues (6-10) which indicated that this method can enhanced the structural diversity of this strain by culturing with amino acids. Cytotoxicity of the isolated compounds were evaluated against a panel of human cancer cell lines.

Antibacterial p-terphenyl and α­pyrone derivates isolated from the marine-derived actinomycete Nocardiopsis sp. HDN154086.

Assisted by OSMAC strategy, one new p-terphenyl and two new α­pyrone derivates, namely nocarterphenyl I (1) and nocardiopyrone D-E (2-3), were obtained and characterized from the marine sediment-derived actinomycete Nocardiopsis sp. HDN154086. The structures of these compounds were determined on the basis of MS, NMR spectroscopic data and single-crystal X-ray diffraction. Compound 1 with a rare 2,2'-bithiazole structure among natural products showed promising activity against five bacteria with MIC values ranging from 0.8 to 1.6 µM and 3 exhibited notable antibacterial activity against MRSA compared the positive control ciprofloxacin.

The Discovery of Acremochlorins O-R from an Acremonium sp. through Integrated Genomic and Molecular Networking.

The fermentation of a soil-derived fungus Acremonium sp. led to the isolation of thirteen ascochlorin congeners through integrated genomic and Global Natural Product Social (GNPS) molecular networking. Among the isolated compounds, we identified two unusual bicyclic types, acremochlorins O (1) and P (2), as well as two linear types, acremochlorin Q (3) and R (4). Compounds 1 and 2 contain an unusual benzopyran moiety and are diastereoisomers of each other, the first reported for the ascochlorins. Additionally, we elucidated the structure of 5, a 4-chloro-5-methylbenzene-1,3-diol with a linear farnesyl side chain, and confirmed the presence of eight known ascochlorin analogs (6-13). The structures were determined by the detailed interpretation of 1D and 2D NMR spectroscopy, MS, and ECD calculations. Compounds 3 and 9 showed potent antibacterial activity against Staphylococcus aureus and Bacillus cereus, with MIC values ranging from 2 to 16 µg/mL.

Novel antifungal talaroenamine L with unusual leptosphaeronyl moiety from marine-derived Talaromyces sp. HDN17-428 via HDACi elicitation.

Vorinostat elicitation of the deep-sea fungus Talaromyces sp. HDN17-428 resulted in the isolation of one new compound, talaroenamine L (1) with unusual leptosphaeronyl moiety and three known compounds (2-4). Structures of 1-4 were confirmed by extensive NMR, HRESIMS and OR calculations. Antimicrobial activities of all compounds were tested in which compounds 1-4 showed substantial antifungal activities with MIC values ranged from 3.1 to 12.5 µM.

Biosynthesis of Atypical Angucyclines Unveils New Ring Rearrangement Reactions Catalyzed by Flavoprotein Monooxygenases.

Six new angucycline structures, including spirocyclione A (1), which contains an unusual oxaspiro[5.5]undecane architecture, and its ring-A-cleaved product spirocyclione B (2), were discovered by heterologous expression of a type II polyketide biosynthetic gene cluster captured from a marine actinomycete strain Streptomyces sp. HDN155000. Three flavoprotein monooxygenases are confirmed to be responsible for the oxidative carbon skeleton rearrangements in the biosynthesis of compounds 1 and 2. The obtained compounds showed promising cytotoxicity against different types of cancer cells.

New cyclic dipeptide discovered from deep-sea derived Aspergillus sp. HDN20-1401.

A new alkaloid named aspergilalkaloid A (1) with pyridoindole hydroxymethyl piperazine dione structure along with six known compounds 2-7 were isolated from deep-sea derived fungus Aspergillus sp. HDN20-1401. The structure including absolute configuration was elucidated by extensive NMR analyses, HRESIMS, ECD calculation, and theoretical NMR calculation with DP4+ analysis. All isolated compounds were tested for antimicrobial and anticancer activity. Aspergilalkaloid A (1) showed inhibitive activity against Bacillus cereus with MIC value of 12.5 µM and weak activity against MRCNS.

Nonenzymatic Self-Assembly Access to Diverse ortho-Quinone Methide-Based Pseudonatural Products.

A nonenzymatic self-assembly program was introduced to explore diverse clavatol-based pseudonatural products (PNPs) in a marine-derived fungus. Intermolecular couplings of the chemoreactive ortho-quinone methide of clavatol with native acceptors led to 14 clavatol-based PNPs with five categories, and compounds 1, 2, 5-10, and 12 are new. In particular, 1 and 2 possessed an unprecedented oxa-angular tetracyclic scaffold with highly oxidized modification and exhibited cytotoxicity. Such a program is proven to be of great advantage in constructing bioactive PNPs.

Enterotype-Specific Effect of Human Gut Microbiota on the Fermentation of Marine Algae Oligosaccharides: A Preliminary Proof-of-Concept In Vitro Study.

The human gut microbiota plays a critical role in the metabolism of dietary carbohydrates. Previous studies have illustrated that marine algae oligosaccharides could be utilized and readily fermented by human gut microbiota. However, the human gut microbiota is classified into three different enterotypes, and how this may affect the fermentation processes of marine algae oligosaccharides has not been studied. Here, using in vitro fermentation and 16 S high-throughput sequencing techniques, we demonstrate that the human gut microbiota has an enterotype-specific effect on the fermentation outcomes of marine algae oligosaccharides. Notably, microbiota with a Bacteroides enterotype was more proficient at fermenting carrageenan oligosaccharides (KOS) as compared to that with a Prevotella enterotype and that with an Escherichia enterotype. Interestingly, the prebiotic effects of marine algae oligosaccharides were also found to be enterotype dependent. Altogether, our study demonstrates an enterotype-specific effect of human gut microbiota on the fermentation of marine algae oligosaccharides. However, due to the availability of the fecal samples, only one sample was used to represent each enterotype. Therefore, our research is a proof-of-concept study, and we anticipate that more detailed studies with larger sample sizes could be conducted to further explore the enterotype-specific prebiotic effects of marine oligosaccharides.