Jiafan Yang

Meroterpenoids are a class of hybrid natural products, biosynthesized from terpenoid fragments and non‐terpenoid precursors, exhibiting a wide range of biological activities, that provide an important source of compounds for new drug development. This review firstly summarizes the update of meroterpenoids from February 2020 to December 2025 by applying a new classification method based on twelve key non‐terpene precursors. A total of 906 new meroterpenoids were reported from 214 studies, while recent synthetic and biosynthetic investigations have further expanded both the accessible chemical space and our mechanistic understanding of this compound class. Among them, biosynthetic pathways originating from 4‐hydroxybenzoic acid and 3,5‐dimethylorsellinic acid were found to be the highest proportion. Statistical analysis shows that over 40% of the cataloged compounds exhibit broad biological activities, with anti‐cancer, anti‐inflammatory, and antimicrobial effects being the top three. The significant structural variety and potent bioactivity of fungal meroterpenoids serve as a sustainable source for novel drug lead compounds.

Depsidones are structurally diverse polyketides with significant pharmacological potential. Their structural variability in the marine-derived fungus Aspergillus sp. SCSIO SX7S7 stems from the substrate promiscuity of key enzymes, particularly the starter-unit acyltransferase (SAT) domain of non-reducing polyketide synthase (NR-PKS). In this study, we combined a metabolic blockade with the inherent biosynthetic flexibility to access rare depsidone derivatives. Inactivation of the highly reducing polyketide synthase (HR-PKS) gene depD redirected metabolic flux to potential branching pathways, leading to the isolation of (i) aspergillol A (1), an unprecedented depsidone featuring a unique benzene substitution, (ii) four new orsellinic acid homodimer-derived depsidones aspergillol B-E (2-5), (iii) a new diphenyl ether derivative aspergillol F (6), and (iv) two known compounds (7 and 8) but lacking complete NMR data from a previous publication. Further structure-activity relationship analyses revealed that the ester linkage in compounds 1-5 is essential for antimicrobial activities, while the distinctive benzene extension in compound 1 is responsible for its significantly enhanced activity. These findings not only expand the known structural diversity of fungal depsidones but also reveal the complex metabolic network underlying their biosynthesis while establishing an effective approach for discovering bioactive natural product scaffolds through rational pathway manipulation.

Furanasperterpenes are characterized by a novel 6/6/6/6/5 pentacyclic skeleton and demonstrate significant lipid-lowering activity. In this study, we elucidate the biosynthetic pathway of furanasperterpene B and the enzymatic basis for the formation of its distinctive pentacyclic scaffold. The pathway diverges at a key branching point through the action of Asp14, a novel NTF2-like isomerase that catalyzes D-ring rearrangement to direct biosynthesis toward furanasperterpenes instead of terretonins. Subsequently, α-ketoglutarate-dependent dioxygenase Asp7 catalyzes hydroxylation and facilitates furan ring formation to construct the 6/6/6/6/5 pentacyclic scaffold.

This study reports the discovery of eight new polyketide natural products from the deep-sea actinomycete Pseudonocardia antarctica SCSIO 07407 and its ΔantB3 mutant strain. Through OSMAC (One Strain Many Compounds)-based fermentation, six new spiroketal acid derivatives, namely, semiantarmycins B-G (1-6) and a spiroketal-polyketoester hybrid (7), were isolated from the wild-type strain. In parallel, a new antarmycin analogue, namely, antarmycin D (8), was obtained from the ΔantB3 mutant strain, in which the glycosyl 2,3-dehydratase encoding gene was disrupted. Structure elucidation using HR-ESIMS, 1D/2D NMR, and biosynthetic analysis revealed 1-3 feature a C-11 epimerized spiroketal core glycosylated with vancosamine or glucose, whereas 6 and 5 exhibit sequential dehydration and reduction at C-12/C-13. Compound 7 is the first reported spiroketal-polyketoester hybrid, and macrodiolide 8 incorporates rhamnose glycosylation along with C-11 methylation. Bioactivity screening revealed that 8 exhibits cytotoxicity against five cancer cell lines, including HCT116, SW480, MCF7, MDA-MB-468, and BT-549 with IC₅₀ values ranging from 2.02 to 7.65 μM. This work expands the chemical diversity of spiroketal acids and macrodiolides, highlighting deep-sea actinomycetes as an underexplored source of structurally unique and biologically active natural products.

Micromonospora, a large group of actinomycetes, is increasingly important in natural products discovery. Genus-based metabologenomic analyses and OSMAC tactics unveiled three known (1, 3, and 6) and three new mintaimycins (2, 4, and 5) from marine-derived Micromonospora sp. SCSIO 80128. All absolute configurations were unambiguously established by X-ray diffraction and their biosynthetic gene cluster (min) was validated by heterologous expression. Bioinformatics and gene inactivation studies support a newly proposed biosynthetic pathway to 1-6.

The rapid emergence of antimicrobial-resistant pathogenic microbes has accelerated the search for novel therapeutic agents. Here we report the discovery of antarmycin A (1), an antibiotic containing a symmetric 16-membered macrodiolide core with two pendant vancosamine moieties, one of which is glucosylated, from deep-sea-derived Pseudonocardia antarctica SCSIO 07407. The biosynthetic gene cluster of 1 was identified on a giant plasmid featuring transferable elements. In-depth biosynthetic investigation enabled us to (i) identify a set of seven genes associated with the product of the vancosamine moiety; (ii) discover two glycosyltransferases dedicated to the transfer of pendant sugars; and (iii) isolate rhamnose-modified antarmycin B (2) and a deglucosylated derivative antarmycin C (3) from genetically engineered mutant strains. Antibacterial assays revealed that 1 displays superior antibacterial properties with potent in vitro activities against the critical priority pathogens, multidrug-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus, fast bacterial killing, insusceptibility to antimicrobial resistance, and high in vivo efficiency in infection models. Mechanistic investigations revealed that 1 disrupts the bacterial cell membrane through a mechanism involving interactions between the vancosamine moieties and membrane-embedded phosphatidylglycerol/phosphatidylethanolamine. The results provide insights into the biological generation of vancosamine in natural products and demonstrate the potential of 1 as an effective lead to address the growing antimicrobial resistance threats.

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC₅₀ values of 0.40-16 μM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 μM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.

Marine-derived fungi are emerging as prolific workhorses of structurally novel natural products (NPs) with diverse bioactivities. However, the limitation of available selection markers hampers the exploration of cryptic NPs. Recyclable markers are therefore valuable assets in genetic engineering programs for awaking silent SM clusters. Here, both pyrG and amdS-based recyclable marker cassettes were established and successfully applied in marine-derived fungi Aspergillus sp. SCSIO SX7S7 and Spiromastix sp. SCSIO F190, respectively. Using pyrG recyclable marker, a markerless 7S7-∆depH strain with a simplified HPLC background was built by inactivating a polyketide synthase (PKS) gene depH and looping out the pyrG recyclable marker after depH deletion. Meanwhile, an amdS recyclable marker system was also developed to help strains that are difficult to use pyrG marker. By employing the amdS marker, a backbone gene spm11 responsible for one major product of Spiromastix sp. SCSIO F190 was inactivated, and the amdS marker was excised after using, generating a relatively clean F190-∆spm11 strain for further activation of novel NPs. The collection of two different recycle markers will guarantee flexible application in marine-derived fungi with different genetic backgrounds, enabling the exploitation of novel structures in various fungi species with different genome mining strategies.

Marine-derived fungi are emerging as attractive producers of structurally novel secondary metabolites with diverse bioactivities. However, the lack of efficient genetic tools limits the discovery of novel compounds and the elucidation of biosynthesis mechanisms. Here, we firstly established an effective PEG-mediated chemical transformation system for protoplasts in two marine-derived fungi, Spiromastix sp. SCSIO F190 and Aspergillus sp. SCSIO SX7S7. Next, we developed a simple and versatile CRISPR-Cas9-based gene disruption strategy by transforming a target fungus with a single plasmid. We found that the transformation with a circular plasmid encoding cas9, a single-guide RNA (sgRNA), and a selectable marker resulted in a high frequency of targeted and insertional gene mutations in both marine-derived fungal strains. In addition, the histone deacetylase gene rpd3 was mutated using the established CRISPR-Cas9 system, thereby activating novel secondary metabolites that were not produced in the wild-type strain. Taken together, a versatile CRISPR-Cas9-based gene disruption method was established, which will promote the discovery of novel natural products and further biological studies.