Isolation of the new polyketide (−)-R-talaropinophiloic acid guided by an integrated metabolomics-dereplication approach

Resorcylic Acid Lactones and Isocoumarin Derivatives from the Marine-Associated Polar Fungus Penicillium sp. OUCMDZ-4014

Marine-associated polar fungi are promising sources of structurally diverse natural products. To investigate polyketide metabolites from the Antarctic moss-derived fungus Penicillium sp. OUCMDZ-4014, HSQC NMR combined with DeepSAT analysis was used to prioritize fractions enriched in cyclic and aromatic polyketides, and chromane-like metabolites. Chromatographic separation yielded ten resorcylic acid lactone-derived aromatic polyketides, including RAL macrolides, ring-opened esters, and isocoumarins, among which compounds 4–7 were new. Their planar structures were established by HRESIMS and 1D/2D NMR analyses. Their chemical structures including configurations were established by HRESIMS, 1D/2D NMR, ECD calculations, 13C NMR calculations, and DP4+ analysis. Isocoumarins 7–10 displayed diverse levels of α-glucosidase inhibition, with compound 9 being the most active (IC50 = 47.0 ± 3.83 μM). Kinetic analysis indicated noncompetitive inhibition by 9 and mixed-type inhibition by 10. Genome mining revealed a putative res biosynthetic gene cluster containing HR-PKS, NR-PKS, and tailoring-enzyme genes. Compound 1 underwent nonenzymatic conversion into 9 under culture-medium conditions, while trace conversion was also observed during concentration, revealing a chemical link between the RAL macrolide and isocoumarin scaffolds, and highlighting the contribution of post-biosynthetic chemical transformation to fungal polyketide diversification.

Integrated molecular networking-guided discovery of antimicrobial secondary metabolites from Thyronectria pinicola

Using an LC-MS/MS-based molecular networking-guided approach, three previously undescribed chlorinated resorcylic acid lactone derivatives (5–7), two new cleistanthane-type diterpenoids (11–12) and a new dimeric derivative (13), together with seven known metabolites, were isolated from a cereal culture of Thyronectria pinicola (Ascomycota: Hypocreales). T. pinicola was isolated from a fruiting body of the devils'tooth mushroom, Hydnellum peckii (Basidiomycota, Thelephorales). The structures of the isolated compounds were elucidated using 1D and 2D NMR spectroscopy and HRMS, and their absolute configurations were established by electronic circular dichroism (ECD) calculations or X-ray crystallography. All metabolites were evaluated for their bioactivities against three major human fungal pathogens, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. The results indicated that compound 1 was the most active substance, with MIC values ranging from 1.5 to 50 µg mL−1 against all three species. In contrast, compounds 5 and 10 displayed only moderate activity against A. fumigatus and C. neoformans.

Molecular docking- Guided metabolic redirection approach to design potential media for production of polyhydroxyalkanoate in Bacillus cereus MTCC25697

Canalesolide A, a Structurally Unique Polyhydroxy Macrolide from the Marine Cyanobacterium Okeania sp. with Potent Antitrypanosomal Activity

The discovery of structurally novel natural products remains central to expanding biologically relevant chemical space, particularly within underexplored marine metabolite classes. Herein, we report the discovery and complete structural elucidation of canalesolide A, a new polyhydroxylated macrolide isolated from the marine cyanobacterium Okeania sp. The compound was identified through an integrated workflow combining phenotypic screening against Trypanosoma brucei and LC-MS/MS-based molecular networking, enabling rapid prioritization of bioactive fractions and dereplication of known metabolite families. Spectroscopic analysis revealed that canalesolide A belongs to the bastimolide-related class of macrolides but exhibits a distinct structural architecture. Its structure was established by integrating ultrahigh-resolution NMR spectroscopy, empirical configurational analysis of polyol systems, targeted model compound synthesis, and controlled chemical degradation and derivatization. This combined strategy resolved stereochemical motifs that were inaccessible by direct analysis of the intact macrolide alone, providing a transferable approach for assigning densely oxygenated marine macrolides. Genome mining identified the putative biosynthetic gene cluster and proposed biosynthetic pathway for a bastimolide-related macrolide. Canalesolide A displays potent, low nanomolar antitrypanosomal activity against human-infective subspecies of T. brucei with rapid elimination of parasites within 1 h at 1 μM. Although moderate mammalian cytotoxicity was observed, preliminary in vivo efficacy/toxicity studies in infected mice suggest a narrow therapeutic window highlighting the need for improved selectivity. This study expands the structural and biosynthetic diversity of polyhydroxylated macrolides and establishes a generalizable framework for resolving stereochemically complex natural products.

N -Acetylcysteine-Conjugated Benzoxazomycins and Hydroxymycotrienin Derivatives from a Hymenoptera-Associated Streptomyces sp. SID10815

As part of our continuing search for antifungal natural products, we investigated the secondary metabolites of Streptomyces sp. SID10815, an actinomycete isolated from a ground-nesting bee-associated environment that exhibited notable antifungal activity in preliminary screenings. Herein, we report the discovery of four new N-acetylcysteine-modified ansamycins (1−4) and three new hydroxymycotrienin analogues (5−7), together with six known ansamycins (8−13), produced by this strain. These metabolites were detected and prioritized through a metabolomics-guided dereplication strategy integrating LC−MS profiling and bioactivity correlation. Their structures were elucidated by comprehensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (1H, 13C, COSY, HSQC, HMBC, and NOESY) in combination with high-resolution mass spectrometry. The newly identified metabolites expand the structural diversity of the ansamycin family and provide a basis for future structure−activity relationship studies of N-acetylcysteine-conjugated ansamycins. These findings define a distinctive ansamycin profile of Streptomyces sp. SID10815 that may serve as a useful chemical signature for future comparative studies of insect-associated actinomycetes.

Tandyukisins K–P, New Decalin Polyketides from Trichoderma longicollum 17007 with Antitubercular Activity Against Mycobacterium tuberculosis H37Ra

Background: Endophytic fungi are important sources of structurally diverse antimicrobial natural products, but their potential to yield antitubercular scaffolds remains insufficiently explored. This study aimed to uncover new decalin polyketides from the endophytic fungus, Trichoderma longicollum 17007, and to evaluate their biological activity. Methods: Feature-based molecular networking (FBMN) analysis of the ethyl acetate extract from rice-based cultures was performed using trichoharzin as a seed compound to guide targeted isolation. Structures were established by HRMS, 1D and 2D NMR spectroscopy, NOESY analysis, and quantum chemical ECD calculations. Cytotoxicity and activity against the avirulent Mycobacterium tuberculosis H37Ra strain were evaluated, and genome mining was performed to identify a candidate biosynthetic gene cluster. Results: Six new decalin polyketides, tandyukisins K–P (1–6), and two known analogues, trichoharzin (7) and tandyukisin J (8), were isolated. Compounds 1–6 are C1-O-acetylated analogues bearing a 3-methylpentenedioate-type acyl side chain. Comparative 13C NMR analysis revealed empirical features useful for assigning side-chain attachment site, double-bond position and geometry. Tandyukisins K (1) and P (6) showed moderate activity against the avirulent M. tuberculosis H37Ra strain, with a MIC value of 12.5 μg/mL. Conclusions: These findings expand the structural diversity of decalin polyketides and provide the first evidence of antitubercular activity by this compound family.