Mpox is a globally prevalent disease that has triggered multiple epidemics over the past few decades, leading to moderate rates of hospitalisation and mortality. Recently, it has re-emerged in several countries, including the Democratic Republic of Congo, and appears to be spreading at an unprecedented pace. The disease is caused by zoonotic double-stranded DNA viruses. Due to its similarities with smallpox, distinguishing between the two can be challenging, though the smallpox vaccine typically provides immunity against Mpox. At the time of writing, no approved treatment for Mpox exists; however, several promising candidates have demonstrated the ability to inhibit viral replication, including resveratrol—a polyphenolic compound found in red wine. This study employs molecular docking and molecular dynamics simulations to assess the effectiveness and stability of nine resveratrol analogues. Additionally, 2D and 3D pharmacophore models were developed for the highest-ranked docked compounds, leading to a composite pharmacophore. A structure–activity relationship analysis was also conducted using these top-performing compounds. The findings suggest that two compounds— (9) [1,1'-biphenyl]-3,4',5-triol and (11) {3-hydroxy-5-[2-(4-hydroxyphenyl)ethenyl]phenyl}oxidanesulfonic acid—exhibit strong binding affinity, with compound 11 potentially forming a stable complex with the thymidylate kinase of the vaccinia virus. Graphical abstract

Fungi represent a prolific source of structurally diverse secondary metabolites, yet the extent to which culture conditions reshape the metabolic profile and functional bioactivity remains incompletely understood. In this exploratory study, ten fungal strains belonging to genera Penicillium and Aspergillus were cultivated in Yeast Extract Sucrose (YES) and Czapek Yeast Autolysate (CYA) media and analysed using untargeted LC-HRMS metabolomics. The objective of this study was to evaluate how culture medium influences metabolic profiles and to investigate medium-dependent metabolic variation and its relation to cytotoxic, antibacterial, and antifungal activities. Global metabolic profiling revealed moderate but statistically significant medium-associated metabolite variation, with discriminant metabolites predominantly enriched under CYA conditions. Putative structural annotation suggested patterns consistent with differential regulation of isoprenoid-derived sterols, terpenoids, alkaloid-like metabolites, and aromatic polyketides. While antimicrobial activities displayed a heterogeneous, strain-dependent pattern with limited correlation to individual metabolites, cytotoxic activity co-varied with metabolite composition in OPLS regression modelling. Sterols and terpenoid-related features emerged as major contributors to cytotoxicity. Given the absence of biological replication and the limited sample size inherent to this pilot study, all findings should be considered hypothesis-generating and interpreted within an exploratory framework. These results suggest that nutrient composition influences biosynthetic pathway activation while functional outcomes remain strongly dependent on strain-specific metabolic capacity. This work provides a systematic framework and targeted hypothesis for future investigations into condition-dependent fungal chemical diversity in natural product discovery.

Natural products from marine and terrestrial organisms provide an important resource for medicinal chemistry and drug discovery. Defined as occurring at depths greater than 200 m, most of the ocean, by area and volume, is comprised of deep-sea environments. These contrasting ecosystems exhibit a wide range of temperature, pressure, and environmental chemistry conditions that harbour high phylogenetic diversity. Here we analyse the global distribution of Marine Natural Products (MNPs) from deep-sea organisms, which reveals chronic undersampling of the deep ocean as a reservoir of new and diverse chemical structures and bioactivity. The sources of 2909 compounds and extracts, compiled from published records, show a sampling bias towards benthic and shallower deep-sea habitats, with relatively few from areas beyond national jurisdictions and a concentration of records along geomorphological features that have been the focus of marine scientific interest such as seamounts and hydrothermal vents. The phylogenetic distribution of deep-sea MNPs is dominated by non-metazoan sources (76% of records) and Ascomycota fungi in particular (55%). Polyketides are the most prevalent metabolites in deep-sea MNPs, and cytotoxic and antibacterial properties are the most commonly reported bioactivities. Our analyses highlight a need for systematic sampling and consistent data reporting to explore potential relationships, if any, between, bioactivity, new chemical structures, phylogeny and deep-sea environmental conditions, which could guide targeted biodiscovery in our planet’s largest biome and enable better assessment of the benefits of protecting deep-sea biodiversity from human impacts.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a leading global threat, escalated now by the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. In search of a novel anti-tubercular agent with a distinct mechanism of action, this study explores deep-sea marine metabolites as potential inhibitors of the F₄₂₀-dependent oxidoreductase Rv1155, a redox enzyme essential for M. tb survival. A total of 2773 marine-derived compounds curated from the CMNPD, Reaxys, and MarinLit databases were screened using an integrated CADD workflow combining molecular docking, in-silico ADMET profiling, and molecular dynamics (MD) simulations. Docking identified 68 metabolites with strong affinity (−10.98 to −15.95 kcal/mol) for the Rv1155 binding pocket, and from which three compounds, Upenamide (CMNPD_22964), Aspyronol (Compound_1749), and Fiscpropionate F (Compound_1796), were shortlisted as hit candidates. Among these, Upenamide displayed the strongest binding (ΔG = −28.56 kcal/mol) with stable RMSD and hydrogen bond persistence during 100 ns MD simulation, while Aspyronol demonstrated a promising ADMET profile comparable to the native cofactor F₄₂₀₂. MM-GBSA analysis further confirmed the strong binding strength (ΔG _bind = −24.77 to −34.07 kcal/mol) for all three hit candidates. These findings confirm the strong and stable interaction of selected deep-sea marine metabolites with Rv1155. This validated screening pipeline established here provides a cost-effective framework for future experimental validation and expansion to additional F₄₂₀-related drug targets in M. tb.

Fungi represent a prolific source of structurally diverse secondary metabolites, yet the extent to which culture conditions reshape the metabolic profile and functional bioactivity remains incompletely understood. In this exploratory study, ten fungal strains cultivated in Yeast Extract Sucrose (YES) and Czapek Yeast Autolysate (CYA) media were analysed using untargeted LC-HRMS metabolomics. This was then combined with multivariate statistical modelling to evaluate medium-dependent metabolic variation and its relation to cytotoxic, antibacterial and antifungal activities. Global metabolic profiling revealed moderate but statistically significant medium-associated metabolite variation, with discriminant metabolites predominantly enriched under CYA conditions. Putative structural annotation suggested patterns consistent with differential regulation of isoprenoid-derived sterols, terpenoids, alkaloid-like metabolites and aromatic polyketides. While antimicrobial activities displayed a heterogeneous, strain-dependent pattern with limited correlation to individual metabolites, cytotoxic activity co-varied with metabolite composition in OPLS regression modelling. Sterols and terpenoid-related features emerged as major contributors to cytotoxicity. Given the absence of biological replication and the limited sample size inherent to this pilot study, all findings should be considered hypothesis-generating and interpreted within an exploratory framework. These results suggest that nutrient composition influences biosynthetic pathway activation while functional outcomes remain strongly dependent on strain-specific metabolic capacity. This work provides a systematic framework and targeted hypothesis for future investigations into condition-dependent fungal chemical diversity in natural product discovery.

Microorganisms are a valuable source of pharmaceutically active chemicals, serving as scaffolds for synthesis as well as lead structures. Investigating novel biomes frequently yields intriguing chemistry; the Atacama Desert in Chile is one such example. This study reports the isolation of a new reduced anthracycline-related compound from the Atacama Desert-derived bacterium Saccharothrix S26. Structural characterisation was achieved by one-dimensional and two-dimensional NMR, HR-LCMS, and X-ray crystallography. The compound was tested against the ESKAPE pathogens, bovine mastitis-related pathogens, and the fungal strain Cryptococcus neoformans, but no antimicrobial activity was observed.