Two novel types of dimeric alkaloids were isolated from the marine sediment-derived mutant strain Saccharopolyspora erythraea SCSIO 07745/Δspo11. Among them, sacchaindol A (1) represents a previously unreported class of dimeric aminoquinolinone alkaloids, whereas sacchaindols B (2) and C [(±)-3] comprise a rare fused 6/6/5/5 tetracyclic indole alkaloid framework. Their structures were elucidated using a combination of spectroscopic analyses, single-crystal X-ray diffraction, and computational methods. Hypothetical biosynthetic pathways for 1-3 were proposed. Notably, sacchaindols C [(±)-3] exhibited anti-inflammatory activity.

Two novel types of dimeric alkaloids were isolated from the marine sediment-derived mutant strain Saccharopolyspora erythraea SCSIO 07745/Delta spo11. Among them, sacchaindol A (1) represents a previously unreported class of dimeric aminoquinolinone alkaloids, whereas sacchaindols B (2) and C [(+/-)-3] comprise a rare fused 6/6/5/5 tetracyclic indole alkaloid framework. Their structures were elucidated using a combination of spectroscopic analyses, single-crystal X-ray diffraction, and computational methods. Hypothetical biosynthetic pathways for 1-3 were proposed. Notably, sacchaindols C [(+/-)-3] exhibited anti-inflammatory activity.

To address the increasingly urgent problem of iodine pollution, we synthesized a nitrogen-rich cage-based covalent organic framework, Cage-COF-TP(T = bis-(tetraoxacalix[2]arene[2]triazine); P = piperazine), for iodine adsorption and release. Structural characterization revealed caged pores with a size of 26.847 & Aring; and interconnected micropores with diameters of 4.527 & Aring;, forming an ordered three-dimensional network of channels. This architecture, enriched with nitrogen and oxygen atoms, provides abundant adsorption sites and electron-rich channels. Owing to these features, Cage-COF-TP demonstrates exceptional iodine adsorption capacities of 1200 mg center dot g-1 from cyclohexane solution and 218 % from vapor. Importantly, the adsorbed iodine rapidly desorbs in ethanol, underscoring the cyclability of the Cage-COF-TP framework. Density functional theory calculations revealed that the excellent physical adsorption performance of cage-based COFs arises from the unique electronic structure and van der Waals interactions associated with the polycyclic cage structure. The consistency between experimental and theoretical results establishes the structural origin of efficient and reversible iodine adsorption in cage-based COFs. These results highlight the potential of cage-based COFs for iodine removal and recovery and demonstrate how cage-based steric effects can be exploited to design high-performance physical adsorbents.

A novel andrastin-type meroterpenoid, dfpenicimeroterpenoid A (1), featuring an unprecedented fused 6/6/6/4/5 pentacyclic skeleton is described, along with four new analogues from marine-derived fungus Penicillium sp. DF71. The structures were established by analysis of their spectroscopic data, single-crystal X-ray diffraction, and quantum chemical calculations of electronic circular dichroism spectra. Compound 2 showed significant pro-angiogenic activity at a concentration of 20 μM, based on a zebrafish model. Furthermore, a plausible biosynthetic pathway for 1 is proposed.

Eight new anthraquinone analogues, namely rishirilide E (1), galvaquinones D-F (2-4), and two pairs of enantiomers, galvaquinones G (5a/5b) and H (6a/6b), together with four known compounds, rishirilide B (7), galvaquinone A (8), lupinacidin A (9), and lupinacidin B (10), were obtained from marine-derived Micromonospora sp. SCSIO 07396 by overexpressing the phosphopantetheinyl transferase (PPTase). Based on comprehensive HRESIMS data, NMR spectroscopic analyses, X-ray diffraction, and ECD calculations, their structures and absolute configurations were unambiguously elucidated. Assays for pro-angiogenic and anti-inflammatory effects in zebrafish models combined with cytotoxicity screening against six human cancer cell lines (PANC-1, TE-1, HL60, A549, MDA-MB-231, and GSC0722), showed that 1 and 5b promoted angiogenesis at 20 μM, 4 had moderate anti-inflammatory activity at 20 μM, and 8 exhibited cytotoxic activity against GSC0722 cells, with an IC50 value of 26.4 μM.

Seven pairs of new enantiomers, Paecilomyces A-G (1-7), were isolated from the deep-sea-derived fungus Paecilomyces sp. YD-8. Their unprecedented structures, featuring symmetric or single C8-aliphatic chain substitutions on the 1,4-epoxynaphthalene-2,3-dicarboxylic acid core, were elucidated via spectroscopic analysis, X-ray diffraction, and ECD calculations. Several enantiomers (1b, 3a, 4a/4b, and 5b) showed better antithrombotic activity at 6.25 μM than aspirin at 124.9 μM in a zebrafish model, highlighting their therapeutic potential. Moreover, plausible biosynthetic pathways of 1-7 were proposed.

Covering: up to Oct, 2025Cinnamoyl-containing non-ribosomal peptides (CCNPs) are characterized by a cinnamoyl group, which is substituted at the ortho position with an alkyl side chain and linked to a peptide scaffold, representing a structurally unique and pharmacologically promising family of microbial natural products. Here, the current knowledge of their chemical diversity, biological activities, and intricate biosynthetic mechanisms is systematically summarized. Their characteristic biosynthetic logic centers on the conserved coupling of a highly reducing type II polyketide synthase (hrPKS II) with a non-ribosomal peptide synthetase (NRPS). Particular emphasis is placed on two fundamental principles: first, the conserved pathway for cinnamoyl benzene ring formation, initiated by an isomerase and proceeding via 6π-electrocyclization catalyzed by three distinct enzymes classes, namely, YsfF (4-hydroxybenzoyl-CoA thioesterase (4-HBT)-like enzymes), Kcn17-19 (DsrE family enzyme components) and YssX/YsfX, thereby providing a reliable signature for genome mining. Second, the remarkable diversity of cinnamoyl tailoring, peptide modification, and NRPS assembly collectively offers substantial opportunities for structural diversification through combinatorial biosynthesis strategies. Elucidating these biosynthetic features has shifted the research paradigm from discovery to rational engineering. However, this shift has not yet translated into comprehensive pharmacological evaluation, as most reported activities have been only briefly assessed, and extensive studies are still needed to fully realize their therapeutic potential. This review not only consolidates recent advances but also provides a strategic framework for future research aimed at unlocking the full potential of these fascinating natural products.

Three new pyrrole alkaloids, streptopyrroles D–F (1–3), along with four known analogs (4–7) were isolated from Sea Anemone-Associated Streptomyces sp. S1502 via an OSMAC (One Strain Many Compounds)-based strategy. Their structures were elucidated through comprehensive spectroscopic analyses, including HRESIMS and 1D/2D NMR experiments (COSY, HSQC, and HMBC), and further confirmed by X-ray crystallography. Biological evaluation identified streptopyrrole (4) as an anti-MRSA (methicillin-resistant Staphylococcus aureus) agent, while 4 and 6 displayed broad-spectrum cytotoxicity and good selectivity against a panel of human cancer cell lines. Notably, 4 and 6 showed particularly potent activity against the lung cancer cell lines H1299, SW1573, and A549, with IC50 values ranging from 5.43 to 16.24 μM. Further mechanistic investigation revealed that both compounds suppress the proliferation of lung cancer cells by inducing cell cycle arrest at the G0/G1 phase and impair metastatic potential by inhibiting migration and invasion. These findings not only expand the structural diversity of marine-derived pyrrole alkaloids but also reveal the anticancer mechanisms of 4 and 6, highlighting their promise as active candidates for further antitumor drug development, particularly in lung cancer.

Photocatalytic reduction of carbon dioxide (CO2) into high-value multicarbon products, such as ethylene (C2H4), remains a significant challenge due to the difficult C-C coupling process. Potassium poly(heptazine imide) (K-PHI) is a promising photocatalyst, yet efficiently exchanging its interlayer cations to tune catalytic selectivity without causing structural degradation is difficult. Herein, an efficient and green supercritical CO2 (SC CO2) assisted ion-exchange strategy was developed to successfully prepare a series of mono-/di-/trivalent cation-doped M-PHI photocatalysts (M = H+, Na+, Sr+, Ca2+, Co2+, Fe3+). Systematic characterizations confirmed that the SC-CO2 treatment successfully achieved in-depth cation substitution without destroying the intrinsic heptazine framework, effectively regulating the interlayer structure and significantly optimizing the photoelectrochemical charge separation. Among the prepared samples, H-PHI exhibited the optimal photocatalytic CO2 reduction performance with an outstanding selectivity toward C2H4 generation. Under simulated sunlight irradiation for 3 h, the yields of CO, CH4, and C2H4 C2H4 C2H4 reached 3564.87, 807.32, and 40.00 μmol·g−1, respectively, significantly outperforming pristine K-PHI and other metal-doped samples. Crucially, isotope-tracing experiments utilizing a SC CO2-DCl treatment detected deuterated CH4 and C2H4 products, providing direct evidence that the hydrogen in the carbon products originates from the introduced protons, thereby elucidating the precise reaction pathway for C-C coupling. This study provides a green and efficient supercritical CO2 ion exchange strategy for the cation engineering of crystalline carbon nitride, and also offers new ideas and methods for designing high-activity photocatalysts for photocatalytic CO2 reduction.

Aromatic polyketides have emerged as an important source of fluorescent natural products, which hold significant value for research and diagnostic applications. In this study, we reported the discovery of three new (5, 6, and 9) and ten known (1-4, 7, 8, and 10-13) fluorescent aromatic polyketides representing seven sets of carbon skeletons. Compounds 3-13 exhibited fluorescence ranging from cyan to orange-yellow and displayed varied behaviors in terms of excitation wavelength, emission wavelength, and Stokes shift, indicating their diverse spectral characteristics and environmental responsiveness. Notably, globismycin A (5) features an unprecedented 2,3-dihydrobenzofuro[4,5,6-de]chromene scaffold. Compound 5 not only exhibited high quantum yields in both water and organic solvents, with visible green fluorescence to the naked eye, but also showed potent selective cytotoxicity against three cancer cell lines. Biosynthetic investigations through a combination of gene inactivation, heterologous expression, and 13C-labeled acetate feeding studies revealed that these fluorescent compounds, despite differing in size and shape, are all derived from a type II polyketide synthase (PKS) gene cluster sgl, and their diverse skeletons are generated through seven distinct cyclization patterns. More importantly, compound 5 uniquely involves a characteristic fungal F-mode first-ring cyclization step, although 5 has been proven to be a bacterial aromatic polyketide. These findings not only provide excellent fluorescent candidates potentially useful for various biological applications but also expand our understanding on the biosynthetic mechanisms driving the production of diverse aromatic polyketides by type II gene clusters.

The structural groups of 2-oxindole and tricyclic 3a-hydroxy-hexahydropyrrolo-[2,3-b]indole (HO-HPI) are important pharmacophores. Chemical synthesis of complex alkaloids containing a 2-oxindole or HO-HPI moiety, especially the latter one, has been a long-standing challenge. Herein, we characterized the P450 enzyme AfnD, and its homologue proteins, HmtT, ClpD, KtzM, and LtzR, as cyclopeptide 2-oxindole and HO-HPI monooxygenases (cpOPMOs) that could introduce a 2-oxindole or HO-HPI moiety into the tryptophan-containing cyclopeptides in a pH-dependent manner. A universal catalytic mechanism was proposed for the five cpOPMOs, in which two conserved residues, Asp and Ser (Thr for LtzR), were proposed to divergently open the epoxide intermediates, thereby forming a 2-oxindole or HO-HPI moiety. Based on this, we constructed ten Asp or Ser/Thr mutants of cpOPMOs, which could synthesize cyclopeptides with an HO-HPI or 2-oxindole structure, selectively, under appropriate reaction conditions. All of the ten cpOPMO mutants exhibited high substrate promiscuities and usually performed well with cyclopeptides that are structurally similar to their native substrates. Overall, our work discovers a group of intriguing P450 enzymes, the cpOPMOs, and provides a powerful enzymatic toolkit for the selective synthesis of HO-HPI- or 2-oxindole-containing cyclopeptides.

The deep-sea-derived Streptomyces atratus SCSIO ZH16 is a promising host for producing nanomole-level anti-tuberculosis ilamycins. However, limited research on regulating the ilamycins biosynthetic gene cluster (BGC) has hindered industrial production. Our previous study found that nitrogen metabolism-related genes were upregulated in strains with enhanced ilamycins production. Since amino acids from nitrogen metabolism are key precursors, we aimed to optimize ilamycins production by balancing BGC expression and nitrogen metabolism. Using RNA-seq and hierarchical clustering, we identified the native promoter P20605 and its modified version P20605-400, which regulate the positive regulator IlaB in ilamycins BGC. To synchronously boost ilamycins synthesis and precursor supply, we analyzed P20605's function via bioinformatics and validated it using an indigoidine biosynthetic model. The engineered strain ΔilaR::P20605-400-ilaB::PermE*-phoP achieved over a dozen-fold increase in ilamycins yield. Fermentation was successfully scaled up in 5-L and 500-L bioreactors, reaching titers of 2,546.4 mg/L and 1,993.9 mg/L, respectively, significantly surpassing previously reported yields. This study highlights the industrial potential of ilamycins and provides insights into enhancing peptide compound production in Streptomyces.

The sensitive and selective identification of nitroaromatic explosives and industrially ubiquitous nitrates, which are harmful to the environment, is crucial from the viewpoints of security and environmental remediation. New multifunctional fluorescent porous materials that can sense nitro-explosives and nitrates are under continuous development. To this end, this study synthesizes 3,10,15-/-3,10,16-tribromotrinaphtho[3.3.3]propellane (TBP) and 4,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,1,3-benzothiadiazole (BB) and employs them as dual building blocks to prepare a porous conjugated microporous polymer (denoted as CMP-TBP-BB) via Suzuki-Miyaura borylation polycondensation. The CMP-TBP-BB synthesis strategy takes advantage of the donor and acceptor characteristics of the propeller-like trinaphtho[3.3.3]propellane moiety in TBP and the benzothiadiazole group in BB, respectively. The unusual two-dimensional conformation of the CMP with propeller-array-structured monomers helps to position the pi components in the crystalline layers and establishes aligned conduction pathways. CMP-TBP-BB exhibits outstanding fluorescence characteristics. Its distinctive two-dimensional skeleton is exploited to fabricate highly aligned donor-acceptor building blocks, which is typically considered a challenging task. The porous CMP acts as a fluorescent sensor for selectively and sensitively detecting electron-deficient nitro-explosives and metal nitrates. Specifically, CMP-TBP-BB is responsive to 2,4,6-trinitrophenol and Fe(NO3)(3) at parts per million levels, and the results of combined experimental and theoretical investigations of its sensing properties highlight its potential as a CMP-based fluorescence probe. Additionally, the dual-function fluorescent CMP probe exhibits remarkable temperature-sensing behavior owing to the high linearity between the fluorescence intensity and temperature, making it an excellent fluorescent thermometer.

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.

Entropy engineering has proven effective in enhancing catalyst electrochemical properties, particularly for the oxygen evolution reaction (OER). Challenges persist, however, in modulating entropy and understanding the dynamic reconfiguration of high‐entropy sulfides during OER. In this study, an innovative in situ corrosion method is introduced to convert low‐valent nickel on a nickel foam substrate into high‐entropy heazlewoodite (HES/NF), significantly boosting OER performance. By synthesizing a series of low‐, medium‐, and high‐entropy heazlewoodites, the intrinsic factors influence catalyst surface evolution and electrocatalytic activity is systematically explored. Employing a combination of in situ and ex situ characterization techniques, it is observed that HES/NF dynamically transforms into a stable hydroxide oxide (MOOH)‐sulfide composite under OER conditions. This transition, coupled with lattice distortion, optimizes the electrostatic potential distribution, ensuring superior catalytic activity and preventing surface sulfide deactivation through the formation of stable HES‐MOOH species. This synergy enables HES/NF to achieve remarkably low overpotentials: 172.0 mV at 100.0 mA cm −2 and 229.0 mV at an extreme current density of 300.0 mA cm −2 . When paired with a Pt/C cathode, HES/NF exhibits rapid kinetics, outstanding stability, and exceptional water‐splitting performance. The scalable, cost‐effective approach paves the way for advanced electrocatalyst design, promising breakthroughs in energy storage and conversion technologies.

The mycobacterial caseinolytic protease (Clp) system has been recognized as a promising therapeutic target. In this study, we identify two novel ilamycin analogs, ilamycin E (ILE) and ilamycin F (ILF), both targeting the ClpC1 component of the ClpC1P1P2 proteasome. ILE potently disrupts ClpC1P1P2-mediated proteolysis, leading to delayed bactericidal activity, while ILF also binds ClpC1, albeit with lower affinity. Notably, we discover and validate a unique mutation in clpX and a novel insertion in clpC1 both conferring resistance to ILE and ILF in mycobacterium by gene editing. Furthermore, ILE can also inhibit the proteolytic activity of ClpXP1P2 in a manner dependent on the substrate's tag sequence and adaptor. This first demonstration of clpX- and clpC1-mediated ilamycins resistance underscores the potential of ilamycins to target multiple components of the Clp protease system, offering a novel dual-target strategy for combating mycobacterial infections.

Objective:Plant-derived terpenoid ginkgolides exhibit significant pharmacological efficacy, however, their extraction remains costly. Given that levopimaradiene is a key biosynthetic precursor to ginkgolides, its high-yield production via heterologous gene expression therefore establishes a critical foundation for scaling up their manufacture. This study primarily aims to enhance the yield of levopimaradiene in Escherichia coli (LB medium) by remodeling the unnatural isopentenol utilization pathway (IUP). Methods:Plasmid construction was driven by the mechanism of homologous recombination, which utilizes recombinase to facilitate the ligation process. The expression of kinase was carried out using type 7 (T7) promoter and isopropyl β-D-1-thiogalactopyranoside (IPTG) as the inducer. The quantification of levopimaradiene produced by E. coli was determined by comparison with a standard curve that we constructed. Results:Combining the selection of kinases, ribosome-binding site (RBS) screening, protein directed evolution and optimization of fermentation parameters, the production of levopimaradiene in E. coli was ultimately enhanced to 2691.3 mg/L, surpassing the highest reported titers of levopimaradiene with 6-fold in E. coli to date. Additionally, the engineered E. coli was designed to collaborate with farnesyl pyrophosphate (FPP) synthase and geranylfarnesyl pyrophosphate (GFPP) synthase to efficiently produce FPP and GFPP for sesquiterpene and sesterterpene synthesis. Conclusion:Our work showcases a combinatorial engineering strategy that employs an IUP-enhanced E. coli chassis for the microbial production of levopimaradiene, as well as other natural terpenoids.

Guided by comprehensive bioinformatic analysis and global molecular networking, four previously undescribed peptidic natural products, pepticinnamins Q-T (1-4), along with two known analogues (5, 6), were isolated from cultures of the marine-derived Streptomyces sp. SCSIO 68065. Heterologous expression of the pcn biosynthetic gene cluster in the engineered chassis strain Streptomyces atratus ZH16NSEPK enabled the production of pepticinnamin analogues and led to the targeted isolation of two undescribed biosynthetic intermediates, pepticinnamins U and V (7, 8), as well as the known compound pepticinnamin M (9). The structures of these compounds were elucidated by spectroscopic analyses (including 1D and 2D NMR), HRESIMS, time-dependent density functional theory electronic circular dichroism (TDDFT-ECD) calculations, single-crystal X-ray diffraction studies, and advanced Marfey's method. Pepticinnamins Q-S (1-3) and U (7) are characterized by an unusual epoxidized cinnamoyl moiety. Comparative genomic analysis with homologous gene clusters allowed the proposal of their plausible biosynthetic pathways. Moreover, the cytochrome P450 monooxygenase Pcn29 was experimentally confirmed to catalyze the key epoxidation of the cinnamoyl moiety through a combination of targeted gene deletion and in vitro enzymatic reconstitution studies.

Spiromarmycin-type natural products are rare fungal tricyclic aromatic polyketides with remarkable biological activities. However, the enzymatic processes for assembling the lactone and pyran ring of spiromarmycin and its analogues are unclear. Here, we identify a rare benzolactone formation process differing from typical thioesterase domain-catalyzed transesterification. In this process, a short-chain dehydrogenase/reductase (SDR-Spm14)-catalyzed reduction on the phenylacetic acid core plays a critical role in promoting the lactonization process. Then, prenyltransferase (Spm5)-catalyzed prenylation on the benzolactone intermediate, along with monooxygenase (Spm6)-mediated epoxidation, produces an epoxide intermediate. Interestingly, a C6 hydroxy preset by a hydroxylase (Spm12) plays a role instead of an epoxide hydrolase, allowing a unique spontaneous anti-Baldwin cyclization and benzopyran formation for producing a toxic final product in the extracellular space and thus avoiding self-toxicity. Furthermore, structural analysis of Spm14 proteins in apo form and in complex with NADP+ indicates dramatic conformational changes for substrate accommodation. Subsequent molecular docking and structure-based mutagenesis analyses reveal a Tyr-based catalytic mechanism and a Lys-assisted substrate binding mode for Spm14. Importantly, Spm14 shows promiscuous substrate specificity toward diverse phenyl ketones with high stereoselectivity, expanding the potential application of Spm14 in the drug precursor synthesis. This study advances the understanding of benzolactone and benzopyran biosynthesis and expands the biocatalytic toolbox for future drug discovery.

Warkmycin (1), a type II polyketide with complex post-modifications, exhibits potent antitumor activity. Through genome mining and biosynthetic investigations, we identified 20 warkmycin derivatives, 17 of which are new. In this study, we have corrected the nomenclature of sugar A in the structure of warkmycin (1) to α-L-oleandrose. We disclose here the biosynthetic pathway of warkmycins with a special emphasis on the spatiotemporal order of post-tailoring steps. Four glycosyltransferases (War8, War7, War10, and War11) sequentially loaded four rare deoxysugar groups: α-L-oleandrose, β-D-olivose, β-D-olivomycose, and β-D-amicetose. Additionally, the cytochrome P450 enzyme War9 catalyzes β-hydroxylation, the acetyltransferase War21 performs sequentially dual O-acetylation, and the carbamoyltransferase War1 facilitates α-L-oleandrose carbamoylation to generate the final product warkmycin (1). In vitro enzyme reaction results showed that War9, War21, and War1 all have good catalytic activity and substrate promiscuity, which are of great value for the modification of complex molecules. Structure-activity relationship (SAR) studies demonstrated the essentiality of these enzymatic modifications for bioactivity. Notably, the intermediate warkmycin Q (18) exhibited superior antitumor activity. This work not only deciphers the complex enzymatic machinery governing polyketide diversification but also provides novel lead compounds for antitumor drug development and enzymatic tools for the engineering of natural products.