Antimicrobial sesterterpenoids with a unique 5/8/6/5 tetracyclic carbon-ring-system and diepoxide polyketides from a deep sea-sediment-sourced fungus Chaetomium globosum SD-347.

Two new sesterterpenoids, sesterchaetins A and B (1 and 2), and two new diepoxide polyketides, chaetoketoics A and B (3 and 4), were characterized from the culture extract of Chaetomium globosum SD-347, a fungal strain derived from deep sea-sediment. Their structures and absolute configurations were unambiguously determined by detailed NMR, mass spectra, and X-ray crystallographic analysis. Compounds 1 and 2 contained a distinctive 5/8/6/5 tetracyclic carbon-ring-system, which represented a rarely occurring natural product framework. The new isolates 1-4 exhibited selective antimicrobial activities against human and aquatic pathogenic bacteria and plant-pathogenic fungi.

Reconstitution of the Early Stage of Chetomin Biosynthesis in Aspergillus fumigatus Leads to the Production of Epipolythiodioxopiperazines.

Using CRISPR-Cas9 technology and a microhomology-mediated end-joining repair system, we substituted genes of the gliotoxin pathway in Aspergillus fumigatus with genes responsible for chetomin biosynthesis from Chaetomium cochliodes, leading to the production of three new epipolythiodioxopiperazines (ETPs). This work represents the first successful endeavor to produce ETPs in a non-native host. Additionally, the simultaneous disruption of five genes in a single transformation marks the most extensive gene knockout event in filamentous fungi to date.

Chaetoxylariones A-G: undescribed chromone-derived polyketides from co-culture of Chaetomium virescens and Xylaria grammica enabled via the molecular networking strategy.

By co-culturing two endophytic fungi (Chaetomium virescens and Xylaria grammica) collected from the medicinal and edible plant Smilax glabra Roxb. and analyzing them with MolNetEnhancer module on GNPS platform, seven undescribed chromone-derived polyketides (chaetoxylariones A-G), including three pairs of enantiomer ones (2a/2b, 4a/4b and 6a/6b) and four optical pure ones (1, 3, 5 and 7), as well as five known structural analogues (8-12), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray diffraction, 13C NMR calculation and DP4+ probability analyses, as well as the comparison of the experimental electronic circular dichroism (ECD) data. Structurally, compound 1 featured an unprecedented chromone-derived sulfonamide tailored by two isoleucine-derived δ-hydroxy-3-methylpentenoic acids via the acylamide and NO bonds, respectively; compound 2 represented the first example of enantiomeric chromone derivative bearing a unique spiro-[3.3]alkane ring system; compound 3 featured a decane alkyl side chain that formed an undescribed five-membered lactone ring between C-7' and C-10'; compound 4 contained an unexpected highly oxidized five-membered carbocyclic system featuring rare adjacent keto groups; compound 7 featured a rare methylsulfonyl moiety. In addition, compound 10 showed a significant inhibition towards SW620/AD300 cells with an IC50 value of PTX significantly decreased from 4.09 µM to 120 nM, and a further study uncovered that compound 10 could obviously reverse the MDR of SW620/AD300 cells.

Anti-inflammatory Polyketides from an Endophytic Fungus Chaetomium sp. UJN-EF006 of Vaccinium bracteatum.

Seven new polyketides including three chromone derivatives (1-3) and four linear ones incorporating a tetrahydrofuran ring (4-7), along with three known compounds (8-10), were obtained from the fermentation of an endophytic fungus (Chaetomium sp. UJN-EF006) isolated from the leaves of Vaccinium bracteatum. The structures of these fungal metabolites have been elucidated by spectroscopic means including MS, NMR and electronic circular dichroism. A preliminary anti-inflammatory screening with the lipopolysaccharide (LPS) induced RAW264.7 cell model revealed moderate NO production inhibitory activity for compounds 1 and 4. In addition, the expression of three LPS-induced inflammatory factors IL-6, iNOS and COX-2 was also blocked by 1 and 4.

Antimicrobial Potential of Different Isolates of Chaetomium globosum Combined with Liquid Chromatography Tandem Mass Spectrometry Chemical Profiling.

The antimicrobial resistance of pathogenic microorganisms against commercial drugs has become a major problem worldwide. This study is the first of its kind to be carried out in Egypt to produce antimicrobial pharmaceuticals from isolated native taxa of the fungal Chaetomium, followed by a chemical investigation of the existing bioactive metabolites. Here, of the 155 clinical specimens in total, 100 pathogenic microbial isolates were found to be multi-drug resistant (MDR) bacteria. The Chaetomium isolates were recovered from different soil samples, and wild host plants collected from Egypt showed strong inhibitory activity against MDR isolates. Chaetomium isolates displayed broad-spectrum antimicrobial activity against C. albicans, Gram-positive, and Gram-negative bacteria, with inhibition zones of 11.3 to 25.6 mm, 10.4 to 26.0 mm, and 10.5 to 26.5 mm, respectively. As a consecutive result, the minimum inhibitory concentration (MIC) values of Chaetomium isolates ranged from 3.9 to 62.5 µg/mL. Liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) analysis was performed for selected Chaetomium isolates with the most promising antimicrobial potential against MDR bacteria. The LC-MS/MS analysis of Chaetomium species isolated from cultivated soil at Assuit Governate, Upper Egypt (3), and the host plant Zygophyllum album grown in Wadi El-Arbaein, Saint Katherine, South Sinai (5), revealed the presence of alkaloids as the predominant bioactive metabolites. Most detected bioactive metabolites previously displayed antimicrobial activity, confirming the antibacterial potential of selected isolates. Therefore, the Chaetomium isolates recovered from harsh habitats in Egypt are rich sources of antimicrobial metabolites, which will be a possible solution to the multi-drug resistant bacteria tragedy.

Hexasome-INO80 complex reveals structural basis of noncanonical nucleosome remodeling.

Loss of H2A-H2B histone dimers is a hallmark of actively transcribed genes, but how the cellular machinery functions in the context of noncanonical nucleosomal particles remains largely elusive. In this work, we report the structural mechanism for adenosine 5'-triphosphate-dependent chromatin remodeling of hexasomes by the INO80 complex. We show how INO80 recognizes noncanonical DNA and histone features of hexasomes that emerge from the loss of H2A-H2B. A large structural rearrangement switches the catalytic core of INO80 into a distinct, spin-rotated mode of remodeling while its nuclear actin module remains tethered to long stretches of unwrapped linker DNA. Direct sensing of an exposed H3-H4 histone interface activates INO80, independently of the H2A-H2B acidic patch. Our findings reveal how the loss of H2A-H2B grants remodelers access to a different, yet unexplored layer of energy-driven chromatin regulation.

Caryophyllene Sesquiterpenes from a Chaetomium globosum Endophyte of the Canadian Medicinal Plant Empetrum nigrum.

Punctaporonins T (1) and U (2), new caryophyllene sesquiterpenes, were isolated with three known punctaporonins, A (3), B (4), and C (5), from the endophytic fungus Chaetomium globosum (TC2-041). The structures and relative configurations of punctaporonins T and U were elucidated based on a combination of HRESIMS, 1D/2D NMR spectroscopic analysis, and X-ray diffraction analysis, while their absolute configuration is presumed to be consistent with the co-isolated 3-5 on biogenetic arguments. Compound 1 showed weak inhibitory activity against both Mycobacterium tuberculosis and Staphylococcus aureus.

Conformational dynamics of the RNA binding channel regulates loading and translocation of the DEAH-box helicase Prp43.

The DEAH-box helicase Prp43 has essential functions in pre-mRNA splicing and ribosome biogenesis, remodeling structured RNAs. To initiate unwinding, Prp43 must first accommodate a single-stranded RNA segment into its RNA binding channel. This allows translocation of the helicase on the RNA. G-patch (gp) factors activate Prp43 in its cellular context enhancing the intrinsically low ATPase and RNA unwinding activity. It is unclear how the RNA loading process is accomplished by Prp43 and how it is regulated by its substrates, ATP and RNA, and the G-patch partners. We developed single-molecule (sm) FRET reporters on Prp43 from Chaetomium thermophilum to monitor the conformational dynamics of the RNA binding channel in Prp43 in real-time. We show that the channel can alternate between open and closed conformations. Binding of Pfa1(gp) and ATP shifts the distribution of states towards channel opening, facilitating the accommodation of RNA. After completion of the loading process, the channel remains firmly closed during successive cycles of ATP hydrolysis, ensuring stable interaction with the RNA and processive translocation. Without Pfa1(gp), it remains predominantly closed preventing efficient RNA loading. Our data reveal how the ligands of Prp43 regulate the structural dynamics of the RNA binding channel controlling the initial binding of RNA.

Chemical diversity and biological activities of specialized metabolites from the genus Chaetomium: 2013-2022.

Chaetomium (Chaetomiaceae), a large fungal genus consisting of at least 400 species, has been acknowledged as a promising resource for the exploration of novel compounds with potential bioactivities. Over the past decades, emerging chemical and biological investigations have suggested the structural diversity and extensive potent bioactivity of the specialized metabolites in the Chaetomium species. To date, over 500 compounds with diverse chemical types have been isolated and identified from this genus, including azaphilones, cytochalasans, pyrones, alkaloids, diketopiperazines, anthraquinones, polyketides, and steroids. Biological research has indicated that these compounds possess a broad range of bioactivities, including antitumor, anti-inflammatory, antimicrobial, antioxidant, enzyme inhibitory, phytotoxic, and plant growth inhibitory activities. This paper summarizes current knowledge referring to the chemical structure, biological activity, and pharmacologic potency of the specialized metabolites in the Chaetomium species from 2013 to 2022, which might provide insights for the exploration and utilization of bioactive compounds in this genus both in the scientific field and pharmaceutical industry.

Chaetomadramines A-E, a class of siderophores with potent neuroprotective activity from the fungus Chaetomium madrasense cib-1.

Five hydroxamate siderophores, chaetomadramines A-E (1-5), along with seven known compounds were isolated from the fermented rice culture of the fungus Chaetomium madrasense cib-1. Compounds 1-5 were structurally elucidated on the basis of spectroscopic data, which were a group of unusual hydroxamate siderophores, bearing a long fatty acyl on the α-NH2 of the Nδ-hydroxylated ornithine. Compounds 2-5 were new. The structural elucidation and spectroscopic data of 1 were reported for the first time. Compounds 2-4 significantly improved the survival rates of PC12 cells in the neuroprotective activity assay at the concentration of 40 µM.

Chaetonigrisins A-L, a group of 3-Indole-1,2-Propanediol derived alkaloids from Chaetomium nigricolor YT-2.

Thirteen new alkaloids (1-13) as well as ten known compounds were isolated from the solid-state fermented rice medium of the fungus Chaetomium nigricolor YT-2. Their structures were elucidated on the basis of spectroscopic data, quantum calculations, and single crystal X-ray crystallographic analysis. Chaetonigrisin A (1) represents an unprecedented carbon skeleton featuring a polycyclic 1H-pyrano[3,2:3,4-]​furo[2,​3-​b]​indole. Chaetonigrisin B (2) displays a unique carbon skeleton with a 1,3­dioxolane bridged-ring. Chaetonigrisin C (3) is a spirocyclic indole alkaloid. Chaetonigrisins D-H (4-8) are a group of asymmetric dimers, formed with two 3-indol-3yl-1,2-propanediol (4-6) or with a 3-indol-3yl-1,2-propanediol and a 3-indol-2yl-1,2-propanediol (7-8) by a pyran ring. Chaetonigrisins I-L (9-12) each contains a 3-indol-3yl-1,2-propanediol or 3-indol-2yl-1,2-propanediol substructure. Chaetonigrisin M (13) is a new quinoline alkaloid. The neuroprotective activity assay showed that at the concentration of 40 µM, compounds (4-7, 11, and 12) improved the cell viability of PC12 cells were 49.26 %, 74.69 %, 74.76 %, 86.63 %, 66.89 %, and 69.92 %, respectively induced by 6-OHDA, compound 7 showed significant neuroprotective activity via upregulation of SOD1 mRNA and Bcl-2 mRNA.

A Review on Bioactive Compounds from Marine-Derived Chaetomium Species.

Filamentous marine fungi have proven to be a plentiful source of new natural products. Chaetomium, a widely distributed fungal genus in the marine environment, has gained much interest within the scientific community. In the last 20 years, many potential secondary metabolites have been detected from marine-derived Chaetomium. In this review, we attempt to provide a comprehensive summary of the natural products produced by marine-derived Chaetomium species. A total of 122 secondary metabolites that were described from 2001 to 2021 are covered. The structural diversity of the compounds, along with details of the sources and relevant biological properties are also provided, while the relationships between structures and their bioactivities are discussed. It is our expectation that this review will be of benefit to drug development and innovation.

High-resolution structures of a thermophilic eukaryotic 80S ribosome reveal atomistic details of translocation.

Ribosomes are complex and highly conserved ribonucleoprotein assemblies catalyzing protein biosynthesis in every organism. Here we present high-resolution cryo-EM structures of the 80S ribosome from a thermophilic fungus in two rotational states, which due to increased 80S stability provide a number of mechanistic details of eukaryotic translation. We identify a universally conserved 'nested base-triple knot' in the 26S rRNA at the polypeptide tunnel exit with a bulged-out nucleotide that likely serves as an adaptable element for nascent chain containment and handover. We visualize the structure and dynamics of the ribosome protective factor Stm1 upon ribosomal 40S head swiveling. We describe the structural impact of a unique and essential m1acp3 Ψ 18S rRNA hyper-modification embracing the anticodon wobble-position for eukaryotic tRNA and mRNA translocation. We complete the eEF2-GTPase switch cycle describing the GDP-bound post-hydrolysis state. Taken together, our data and their integration into the structural landscape of 80S ribosomes furthers our understanding of protein biogenesis.

Cytochalasan Alkaloids as TRAIL Sensitizers from an Endophytic Fungus Chaetomium sp.

Two new cytochalasans with a rare 6/6/5/5/7 pentacyclic ring system, named chaetoconvosins C-D (1: -2: ), together with two known congeners (3: -4: ), were isolated from the fermentation of an endophytic fungus, Chaetomium sp. SG-01, harbored in the fibrous roots of Schisandra glaucescens Diels. Their structures including the absolute configuration were elucidated by extensive spectroscopic (HRESIMS, NMR, and ECD) and X-ray crystallographic analyses. The TRAIL-resistance-overcoming activity of 1: -4: in a TRAIL-resistant HT29 colorectal cancer cell line was evaluated, which revealed that co-treatment of 1: -4: at 50 µM with TRAIL (150 ng/mL) reduced the HT29 cell viability by 19.0%, 24.1%, 17.9%, and 15.5%, respectively, compared to treatment with 1: -4: alone.

Armochaetoglasins J and K: new cytochalasans from Chaetomium globosum.

Two novel cytochalasans, armochaetoglasin J (1) and armochaetoglasin K (2), along with 14 known analogues (3-16) were isolated from Chaetomium globosum. Their structures were elucidated by HRESIMS, NMR spectroscopy, single-crystal X-ray crystallography, and ECD spectra. Armochaetoglasins J and K were found to be inactive against the HepG2, HT-29, K562, HL-60, and A549 cancer cell lines.

Rubichaetoglobin A, a new cytochalasan alkaloid isolated from the plant endophytic fungus Chaetomium tectifimeti S104.

Rubichaetoglobin A (1), a new cytochalasan alkaloid, together with nine closely related known ones (2-10), were isolated from the ethyl acetate extracts of the endophytic fungus Chaetomium tectifimeti S104 harbored in the root of Rubia podantha Diels. Their structures were elucidated based on comprehensive spectroscopic analysis. All isolated compounds were tested for cytotoxic, antibacterial, and nitric oxide inhibitory activities. The results showed that 2, 4, and 5 possessed moderate cytotoxicity against MDA-MB-231 cells with the IC50 values of 19.14, 11.43, and 10.27 µM, respectively.

Cytotoxic and antibacterial depsidones from the endophytic fungus Chaetomium brasiliense isolated from Thai rice.

Four new depsidones, mollicellins V-Y (1-4), together with eight known depsidones (5-12) were isolated from the endophytic fungus, Chaetomium brasiliense, detached from stems of Thai rice. Their structures were determined by extensive spectroscopic methods. Mollicellins X, H, and F (3, 8 and 10) showed potent cytotoxicity against the human oral epidermoid carcinoma (KB) cell line, and mollicellin F (10) also showed a potent cytotoxicity against the human hepatocellular carcinoma (HepG2) cell line. Besides, mollicellin B (11) exhibited cytotoxicity against the colorectal adenocarcinoma (HT-29) cell line. Moreover, most of the isolated depsidones displayed potent antibacterial activity against Gram-positive bacteria, Bacillus cereus and Bacillus subtilis, and several of them showed moderate activity against Methicillin-resistant Staphylococcus aureus (MRSA) and clinical isolates of S. aureus. In addition, a few of them also showed moderate activity against a Gram-negative bacteria Pseudomonas aeruginosa.

Anti-HIV Compounds from the Deep-Sea-Derived Fungus Chaetomium globosum.

Chemical investigation on the deep-sea-derived fungus Chaetomium globosum led to the isolation of nine compounds. By extensive analyses of the 1D and 2D NMR as well as HR-ESI-MS spectra, their structures were elucidated as xylariol A (1), 1,3-dihydro-4,5,6-trihydroxy-7-methylisobenzofuran (2), epicoccone B (3), epicoccolide B (4), chaetoglobosin G (5), chaetoglobosin Fex (6), cochliodone A (7), cochliodone B (8), and chaetoviridin A (9), assorting as four phenolics (1-4), two cytochalosans (5-6), and three azaplilones (7-9). Compounds 1-3 were firstly reported from C. globosum. Under the concentrations of 20 µg/mL, 1, 2, and 3 exhibited potent in vitro anti-HIV activity with the inhibition rates of 70 %, 75 %, and 88 %, respectively.

Aureonitol Analogues and Orsellinic Acid Esters Isolated from Chaetomium elatum and Their Antineuroinflammatory Activity.

Overexpression of various pro-inflammatory factors in microglial cells tends to induce neurodegenerative diseases, for which there is no effective therapy available. Aureonitol (1) and seven analogues, including six previously undescribed [elatumenol A-F (2-4, 6-8, respectively)], along with two new orsellinic acid esters [elatumone A and B (9 and 10)], were isolated from Chaetomium elatum. The structures of the compounds were established through comprehensive analysis of spectroscopic data, including high-resolution mass spectra and one- and two-dimensional NMR, and absolute configurations determined by the Mosher method, dimolybdenum tetraacetate-induced circular dichroism, and theoretical calculations including electronic circular dichroism and NMR. Metabolites 3, 4, 7, and 8 exhibited antineuroinflammatory activity by attenuating the production of inflammatory mediators, such as nitric oxide, interleukin-6, interleukin-1ß, tumor necrosis factor-α, and reactive oxygen species. Western blot results indicated 8 decreases the level of inducible nitric oxide synthase and cyclooxygenase-2 and suppresses the expression of Toll-like receptor 4 and nuclear factor kappa-B (NF-κB) as well as the phosphorylation of the inhibitor of NF-κB and p38 mitogen-activated protein kinases in lipopolysaccharide-activated BV-2 microglial cells.

Effect of molecular weight on the antibacterial activity of polysaccharides produced by Chaetomium globosum CGMCC 6882.

This study investigated the effect of molecular weight on antibacterial activity of polysaccharides. Results showed that low molecular weight (3.105 × 104 Da) polysaccharide (GCP-2) had higher inhibitory effects against Escherichia coli and Staphylococcus aureus than high molecular weight (5.340 × 104 Da) polysaccharide (GCP-1). Meanwhile, antibacterial activities of GCP-2 and GCP-1 against S. aureus were higher than those of E. coli. Minimum inhibitory concentrations (MICs) of GCP-1 against E. coli and S. aureus were 2.0 mg/mL and 1.2 mg/mL, and MICs of GCP-2 against E. coli and S. aureus were 1.75 mg/mL and 0.85 mg/mL, respectively. Antibacterial mechanisms investigation revealed that GCP-2 and GCP-1 influenced cell membrane integrity, Ca2+-Mg2+-ATPase activity on cell membrane and calcium ions in cytoplasm of E. coli and S. aureus, but not cell wall. Present work provided important implications for future studies on development of antibacterial polysaccharides based on molecular weight feature.