Anti-Agrobacterium tumefactions sesquiterpene derivatives from the marine-derived fungus Trichoderma effusum.

Agrobacterium tumefaciens can harm various fruit trees, leading to significant economic losses in agricultural production. It is urgent to develop new pesticides to effectively treat this bacterial disease. In this study, four new sesquiterpene derivatives, trichoderenes A-D (1-4), along with six known compounds (5-10), were obtained from the marine-derived fungus Trichoderma effusum. The structures of 1-4 were elucidated by extensive spectroscopic analyses, and the calculated ECD, ORD, and NMR methods. Structurally, the hydrogen bond formed between the 1-OH group and the methoxy group enabled 1 to adopt a structure resembling that of resorcylic acid lactones, thereby producing the ECD cotton effect. Compound 3 represents the first example of C12 nor-sesquiterpene skeleton. Compounds 1-10 were tested for their antimicrobial activity against A. tumefactions. Among them, compounds 1-3 and 8-10 exhibited inhibitory activity against A. tumefactions with MIC values of 3.1, 12.5, 12.5, 6.2, 25.0, and 12.5 µg/mL, respectively.

Secondary Metabolites from Marine-Derived Fungus Penicillium rubens BTBU20213035.

Two new polyketide derivatives, penirubenones A and B (1 and 2), and two naturally rare amino-bis-tetrahydrofuran derivatives, penirubenamides A and B (3 and 4), together with nine known compounds (5-13) were isolated from the marine-derived fungus Penicillium rubens BTBU20213035. The structures were identified by HRESIMS and 1D and 2D NMR analyses, and their absolute configurations were determined by a comparison of experimental and calculated electronic circular dichroism (ECD) spectroscopy and 13C NMR data. We found that 6 exhibited antibacterial activity against Staphylococcus aureus, with an MIC value of 3.125 µg/mL, and 1 and 2 showed synergistic antifungal activity against Candida albicans at 12.5 and 50 µg/mL with 0.0625 µg/mL rapamycin.

New Secondary Metabolites from Marine-Derived Fungus Talaromyces minnesotensis BTBU20220184.

Six new compounds, talamitones A and B (1 and 2), demethyltalamitone B (3), talamiisocoumaringlycosides A and B (4 and 5), and talaminaphtholglycoside (6), together with six known compounds (7-12), were isolated from the marine-derived fungus Talaromyces minnesotensis BTBU20220184. The new structures were characterized by using HRESIMS and NMR. This is the first report of isocoumaringlycoside derivatives from a fungus of the Talaromyces genus. Compounds 5, 6, and 9 showed synergistic antibacterial activity against Staphylococcus aureus.

Miniaturized Cultivation Profiling (MATRIX)-Facilitated Discovery of Noonazines A-C and Noonaphilone A from an Australian Marine-Derived Fungus, Aspergillus noonimiae CMB-M0339.

Subjecting the Australian marine-derived fungus Aspergillus noonimiae CMB-M0339 to cultivation profiling using an innovative miniaturized 24-well plate format (MATRIX) enabled access to new examples of the rare class of 2,6-diketopiperazines, noonazines A-C (1-3), along with the known analogue coelomycin (4), as well as a new azaphilone, noonaphilone A (5). Structures were assigned to 1-5 on the basis of a detailed spectroscopic analysis, and in the case of 1-2, an X-ray crystallographic analysis. Plausible biosynthetic pathways are proposed for 1-4, involving oxidative Schiff base coupling/dimerization of a putative Phe precursor. Of note, 2 incorporates a rare meta-Tyr motif, typically only reported in a limited array of Streptomyces metabolites. Similarly, a plausible biosynthetic pathway is proposed for 5, highlighting a single point for stereo-divergence that allows for the biosynthesis of alternate antipodes, for example, the 7R noonaphilone A (5) versus the 7S deflectin 1a (6).

Anti-neuroinflammatory andrastin-type meroterpenoids from the marine-derived fungus Penicillium chrysogenum HNNU w0032.

A new andrastin-type meroterpenoid penimerodione A (1), and three known analogues (2-4), were isolated from the culture of a marine-derived fungus Penicillium chrysogenum HNNU w0032 by the guidance of MS/MS-based molecular networking. The planar structure of 1 was established by extensive NMR spectroscopic and HRESIMS analyses, and the absolute configuration was elucidated by a single-crystal X-ray diffraction. Compound 1 showed significant inhibitory effect on NO production in LPS-stimulated BV-2 macrophages with an IC50 value of 5.9 ± 0.3 µM. The Western blot result revealed that compound 1 exerted an anti-neuroinflammatory effect via the MAPK signalling pathway.

Ent-eudesmane sesquiterpenoids with anti-neuroinflammatory activity from the marine-derived fungus Eutypella sp. F0219.

In this study, twenty-three ent-eudesmane sesquiterpenoids (1-23) including fifteen previously undescribed ones, named eutypelides A-O (1-15) were isolated from the marine-derived fungus Eutypella sp. F0219. Their planar structures and relative configurations were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of the previously undescribed compounds were determined by single-crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Structurally, eutypelide A (1) is a rare 1,10-seco-ent-eudesmane, whereas 2-15 are typically ent-eudesmanes with 6/6/-fused bicyclic carbon nucleus. The anti-neuroinflammatory activity of all isolated compounds (1-23) was accessed based on their ability to NO production in LPS-stimulated BV2 microglia cells. Compound 16 emerged as the most potent inhibitor. Further mechanistic investigation revealed that compound 16 modulated the inflammatory response by decreasing the protein levels of iNOS and increasing ARG 1 levels, thereby altering the iNOS/ARG 1 ratio and inhibiting macrophage polarization. qRT-PCR analysis showed that compound 16 reversed the LPS-induced upregulation of pro-inflammatory cytokines, including iNOS, TNF-α, IL-6, and IL-1ß, at both the transcriptional and translational levels. These effects were linked to the inhibition of the NF-κB pathway, a key regulator of inflammation. Our findings suggest that compound 16 may be a potential structure basis for developing neuroinflammation-related disease therapeutic agents.

Chemical Constituents and Anticancer Activities of Marine-Derived Fungus Trichoderma lixii.

The fungal genus Trichoderma is a rich source of structurally diverse secondary metabolites with remarkable pharmaceutical properties. The chemical constituents and anticancer activities of the marine-derived fungus Trichoderma lixii have never been investigated. In this study, a bioactivity-guided investigation led to the isolation of eleven compounds, including trichodermamide A (1), trichodermamide B (2), aspergillazine A (3), DC1149B (4), ergosterol peroxide (5), cerebrosides D/C (6/7), 5-hydroxy-2,3-dimethyl-7-methoxychromone (8), nafuredin A (9), and harzianumols E/F (10/11). Their structures were identified by using various spectroscopic techniques and compared to those in the literature. Notably, compounds 2 and 5-11 were reported for the first time from this species. Evaluation of the anticancer activities of all isolated compounds was carried out. Compounds 2, 4, and 9 were the most active antiproliferative compounds against three cancer cell lines (human myeloma KMS-11, colorectal HT-29, and pancreas PANC-1). Intriguingly, compound 4 exhibited anti-austerity activity with an IC50 of 22.43 µM against PANC-1 cancer cells under glucose starvation conditions, while compound 2 did not.

A novel polycyclic quinazoline and three quinolines alkaloids from marine-derived fungus trichoderma longibrachiatum QD01 with anti-bacterial and anti-quorum sensing activities.

A novel polycyclic quinazoline alkaloid (1) along with one new natural quinoline alkaloid (2) and two known quinoline alkaloids (3,4) were isolated from the marine-derived fungus Trichoderma longibrachiatum QD01. Structural determinations of those isolates were established by comprehensive spectroscopic analyses and literature comparison. Single-crystal X-ray diffraction analysis of novel compound verified its structure and stereochemistry, representing the first characterised crystal structure of a trimeric-type of tetrahydroquinazoline. Compound 4 exhibited potential antibacterial and anti-quorum sensing activity against C. violaceum and C. violaceum CV026. The sub-MIC of 4 observably decreased the violacein production in C. violaceum CV026 by 55% on 15 µg/mL. Furthermore, molecular docking results revealed that 4 has stronger binding interactions with CviR receptor than ligand C6-HSL with lower binding energy of -8.68 kcal/mol. Hydrogen bond and π-π interactions formed by Trp84, Tyr88, Trp111, and Phe126 were predicted to play an important role in the inhibition against C. violaceum CV026.

Marine-Fungus-Derived Natural Compound 4-Hydroxyphenylacetic Acid Induces Autophagy to Exert Antithrombotic Effects in Zebrafish.

Marine natural products are important sources of novel drugs. In this study, we isolated 4-hydroxyphenylacetic acid (HPA) from the marine-derived fungus Emericellopsis maritima Y39-2. The antithrombotic activity and mechanism of HPA were reported for the first time. Using a zebrafish model, we found that HPA had a strong antithrombotic activity because it can significantly increase cardiac erythrocytes, blood flow velocity, and heart rate, reduce caudal thrombus, and reverse the inflammatory response caused by Arachidonic Acid (AA). Further transcriptome analysis and qRT-PCR validation demonstrated that HPA may regulate autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway to exert antithrombotic effects.

Novel anti-inflammatory diketopiperazine alkaloids from the marine-derived fungus Penicillium brasilianum.

Diketopiperazine alkaloids have proven the most abundant heterocyclic alkaloids up to now, which usually process diverse scaffolds and rich biological activities. In our search for bioactive diketopiperazine alkaloids from marine-derived fungi, two novel diketopiperazine alkaloids, penipiperazine A (1) and its biogenetically related new metabolite (2), together with a known analogue neofipiperzine C (3), were obtained from the strain Penicillium brasilianum. Their planar structures and absolute configurations were elucidated by extensive spectroscopic analyses, 13C NMR calculation, Marfey's, ECD, and ORD methods. Compound 1 featured a unique 6/5/6/6/5 indole-pyrazino-pyrazino-pyrrolo system, and its plausible biogenetic pathway was also proposed. Additionally, compounds 1-3 have been tested for their inflammatory activities. 1 and 2 significantly inhibited the release of NO and the expression of related pro-inflammatory cytokines on LPS-stimulated RAW264.7 cells, suggesting they could be attracting candidate for further development as anti-inflammatory agent. KEY POINTS: • A novel diketopiperazine alkaloid featuring a unique 6/5/6/6/5 indole-pyrazino-pyrazino-pyrrolo system was isolated from the marine fungus Penicillium brasilianum. • The structure of 1 was elucidated by detailed analysis of 2D NMR data, 13C NMR calculation, Marfey's, ECD, and ORD methods. • Compounds 1 and 2 significantly inhibited the release of NO and the expression of related pro-inflammatory cytokines on LPS-stimulated RAW264.7 cells.

New fusidane-type nortriterpenoids from the Arctic marine-derived fungus Simplicillium lamellicola culture medium with their inhibitory effect on benign prostatic hyperplasia.

Three new fusidane-type nortriterpenoids, simplifusinolide A, 24-epi simplifusinolide A, and simplifusidic acid L (1-3), were isolated from the EtOAc extract of the Arctic marine-derived fungus Simplicillium lamellicola culture medium, together with fusidic acid (4) and 16-O-deacetylfusicid acid (5). The structures of the isolated compounds were elucidated by NMR and MS analyses. The absolute configurations of compounds 1-3 were established by the quantum mechanical calculations of electronic circular dichroism and gauge-including atomic orbital NMR chemical shifts, followed by DP4 + analysis. Benign prostatic hyperplasia (BPH) is a major urological disorder in men worldwide. The anti-BPH potentials of the isolated compounds were evaluated using BPH-1 and WPMY-1 cells. Treatment with simplifusidic acid L (3) and fusidic acid (4) significantly downregulated the mRNA levels of the androgen receptor (AR) and its downstream effectors, inhibiting the proliferation of BPH-1 cells. Specifically, treatment with 24-epi simplifusinolide A (2) significantly suppressed the cell proliferation of both BPH-1 and DHT-stimulated WPMY-1 cells by inhibiting AR signaling. These results suggest the potential of 24-epi simplifusinolide A (2), simplifusidic acid L (3) and fusidic acid (4) as alternative agents for BPH treatment by targeting AR signaling.

Curvularin derivatives from the marine mangrove derived fungus Penicillium sumatrense MA-325.

Sumalarins D-G (1-4), four previously undescribed curvularin derivatives, along with two known related metabolites, curvularin (5) and dehydrocurvularin (6), were isolated and identified from the mangrove-derived fungus Penicillium sumatrense MA-325. Among them, sumalarin D (1) represents a unique example of curvularin derivative featuring a 5-methylfuran-2-yl-methyl group. Their structures were elucidated based on analysis of NMR and MS data as well as comparison of ECD spectra and quantum chemical calculations of NMR, and compound 1 was confirmed by X-ray crystallographic analysis. Compounds 1, 2, 5, and 6 are active against aquatic pathogenic bacteria Vibrio alginolyticus and V. harveyi with MIC values ranging from 4 to 64 µg/mL, while compound 6 is cytotoxic against tumor cell lines 5673, HCT 116, 786-O, and Hela with IC50 values of 3.5, 10.6, 10.9, and 14.9 µM, respectively.

Cytotoxic pyrone derivatives from the deep-sea-derived fungus Cladosporium halotolerans FS702.

Two new compounds (R)-6-((8S)-hydroxypropyl)-2-methyl-5,6-dihydro-4H-pyran-4-one (1) and (R)-6-((8R)-hydroxypropyl)-2-methyl-5,6-dihydro-4H-pyran-4-one (2), together with four known compounds were isolated from the marine-derived fungus Cladosporium halotolerans FS702. The structures of these compounds were determined on the basis of extensive spectroscopic analysis including 1D/2D NMR, IR, UV, HRESIMS, ECD calculations as well as the modified Mosher's method. Cytotoxic assay results showed that compound 2 had significant cytotoxic activity against SF-268, MCF-7, HepG-2, and A549 cells lines with IC50 values of 0.16, 0.47, 0.33 and 0.23 µM, respectively.

3-Carboxy-indole derivatives from the deep-sea-derived fungus Phomopsis tersa FS441.

Three new compounds phomtersines A-C (1-3) together with nine known compounds were isolated from the marine-derived fungus Phomopsis tersa FS441. Their structures were sufficiently established by spectroscopic methods, including extensive 1D and 2D NMR techniques and modified Snatzke's method. Moreover, compounds 1-12 were evaluated for cytotoxic and anti-inflammatory activities. As a result, phomtersine B (2) and the known compound 10 showed moderate cytotoxic activity against the four tested cell lines with IC50 values ranging from 20.21 to 36.53 µM, and phomtersine A (1) exhibited moderate inhibitory activity against LPS-induced NO production.

New Eremophilane-Type Sesquiterpenes from the Marine Sediment-Derived Fungus Emericellopsis maritima BC17 and Their Cytotoxic and Antimicrobial Activities.

The fungal strain BC17 was isolated from sediments collected in the intertidal zone of the inner Bay of Cadiz and characterized as Emericellopsis maritima. On the basis of the one strain-many compounds (OSMAC) approach, four new eremophilane-type sesquiterpenes (1-4), together with thirteen known derivatives (5-17) and two reported diketopiperazines (18, 19), were isolated from this strain. The chemical structures and absolute configurations of the new compounds were determined through extensive NMR and HRESIMS spectroscopic studies and ECD calculation. Thirteen of the isolated eremophilanes were examined for cytotoxic and antimicrobial activities. PR toxin (16) exhibited cytotoxic activity against HepG2, MCF-7, A549, A2058, and Mia PaCa-2 human cancer cell lines with IC50 values ranging from 3.75 to 33.44 µM. (+)-Aristolochene (10) exhibited selective activity against the fungal strains Aspergillus fumigatus ATCC46645 and Candida albicans ATCC64124 at 471 µM.

A new anthraquinone derivative from the marine fish-derived fungus Alternaria sp. X112.

A new anthraquinone, altermodinacid A (1), and five known derivatives, pachybasic acid (2), emodic acid (3), emodin (4), phomarin (5), and 1,7-dihydroxy-3-methylanthracene-9,10-dione (6), were discovered from a halotolerant fungus Alternaria sp. X112 isolated from a marine fish Gadus macrocephalus. Their structures were determined by analysing MS and NMR data. The cytotoxic effect, antiagricultural pathogens activity, antibacterial activity and quorum sensing inhibitory potential of new compound 1 were evaluated.

Novel citrinin derivatives from fungus Penicillium sp. TW131-64 and their antimicrobial activities.

Six new citrinin derivatives (1, 2, 4, 10, 11, and 16), along with fourteen known analogues, were acquired from Penicillium sp. TW131-64, a marine-derived fungus strain. The chemical structures of new compounds were identified through adopting various spectroscopic methods in combination with X-ray diffraction technology and comparison of the experimental electronic circular dichroism (ECD) with calculated ones. Among them, compounds 1-4 were nitrogen-containing citrinin derivatives existing in enantiomers which were resolved by chiral chromatography. A putative biosynthetic pathway for compounds 1-4 was proposed. Additionally, the antimicrobial activities of these compounds were detected by the broth microdilution assays. Citrinin derivatives 1, 2, 4 and their corresponding enantiomers (1a, 2a, 4a, 1b, 2b, and 4b) exhibited potent antimicrobial activities towards Helicobacter pylori standard strains and multidrug-resistant strains (MIC values ranging from 0.25 to 8 µg/mL), which were comparable or even better than metronidazole. Moreover, compounds 1a and 1b also showed remarkable broad antimicrobial effects towards Staphylococcus aureus, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, vancomycin-resistant Enterococcus faecium (VRE), and Candida albicans. In summary, our studies demonstrated that citrinin enantiomers 1a-4a and 1b-4b, especially 1a and 1b, can be lead compounds in the research and development (R & D) of novel antimicrobial drugs. KEY POINTS: • 3 novel nitrogen-containing citrinin derivatives (1, 2, 4) were isolated. • citrinin derivatives 1-4 in enantiomers were resolved by chiral chromatography. • citrinin derivatives 1a and 1b showed broad and significant antimicrobial effects.

Anthraquinone Derivatives and Other Aromatic Compounds from Marine Fungus Asteromyces cruciatus KMM 4696 and Their Effects against Staphylococcus aureus.

New anthraquinone derivatives acruciquinones A-C (1-3), together with ten known metabolites, were isolated from the obligate marine fungus Asteromyces cruciatus KMM 4696. Acruciquinone C is the first member of anthraquinone derivatives with a 6/6/5 backbone. The structures of isolated compounds were established based on NMR and MS data. The absolute stereoconfigurations of new acruciquinones A-C were determined using ECD and quantum chemical calculations (TDDFT approach). A plausible biosynthetic pathway of the novel acruciquinone C was proposed. Compounds 1-4 and 6-13 showed a significant antimicrobial effects against Staphylococcus aureus growth, and acruciquinone A (1), dendryol B (4), coniothyrinone B (7), and ω-hydroxypachybasin (9) reduced the activity of a key staphylococcal enzyme, sortase A. Moreover, the compounds, excluding 4, inhibited urease activity. We studied the effects of anthraquinones 1, 4, 7, and 9 and coniothyrinone D (6) in an in vitro model of skin infection when HaCaT keratinocytes were cocultivated with S. aureus. Anthraquinones significantly reduce the negative impact of S. aureus on the viability, migration, and proliferation of infected HaCaT keratinocytes, and acruciquinone A (1) revealed the most pronounced effect.

Four previously undescribed diketopiperazines from marine fungus Aspergillus puniceus FAHY0085 and their effects on liver X receptor α.

Four previously undescribed diketopiperazine-type alkaloids including one oxepin-containing diketopiperazine-type alkaloid, oxepinamide L (1), three 4-quinazolinone alkaloids, puniceloids E-G (10-12), together with 12 known analogues, protuboxepin D (2), oxepinamides D-G, J-K and I (3-9), puniceloids B-D (13-15) and protubonine B (16), were isolated from the culture of the marine-derived fungus Aspergillus puniceus FAHY0085. The structures of the previously undescribed compounds were comprehensively elucidated by detailed interpretation of their NMR and HRESIMS data. Their absolute configurations were unambiguously determined by ROESY experiments, Marfey's method, calculated ECD experiments and single-crystal X-ray diffraction analysis. Compounds (3-4, 6-8, 14-15) were evaluated for their cytotoxic activity against HepG2, MCF-7, SW1116 and HeLa cells and compound 6 and 14 showed moderate cytotoxic activity against HeLa cells with IC50 49.61 ± 2.91 and 28.38 ± 1.57 µM, respectively. Compounds (1-8, 11-15) were screened for their transcriptional activation of liver X receptor α and compound 11 with known compounds 13-15 showed significant transcriptional activation of liver X receptor α with EC50 values in the range 2-50 µM.

Natural products from marine fungi as a source against agricultural pathogenic fungi.

There are many kinds of agricultural pathogenic fungi, which may belong to pathogenic fungi in different species, such as Fusarium, Alternaria, Colletotrichum, Phytophthora, and other agricultural pathogens. Pathogenic fungi from different sources are widely distributed in agriculture, which threaten the lives of crops around the world and caused great damage to agricultural production and economic benefits. Due to the particularity of the marine environment, marine-derived fungi could produce natural compounds with unique structures, rich diversities, and significant bioactivities. Since marine natural products with different structural characteristics could inhibit different kinds of agricultural pathogenic fungi, secondary metabolites with antifungal activity could be used as lead compounds against agricultural pathogenic fungi. In order to summarize the structural characteristics of marine natural products against agricultural pathogenic fungi, this review systematically overview the activities against agricultural pathogenic fungi of 198 secondary metabolites from different marine fungal sources. A total of 92 references published from 1998 to 2022 were cited. KEY POINTS: • Pathogenic fungi, which could cause damage to agriculture, were classified. • Structurally diverse antifungal compounds from marine-derived fungi were summarized. • The sources and distributions of these bioactive metabolites were analyzed.