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Moringadepsin ( 6 ) and chaetone B ( 7 ) were isolated by us in the course of a conventional chemical screening of Morinagamyces vermicularis CBS 303.81, a fungus belonging to the relatively underexplored family Schizotheciaceae of the phylum Ascomycota. Since these metabolites did not account for the antifungal activity observed in a crude extract of this fungus, we utilized an MS/MS-based molecular networking approach to get a thorough insight into the secondary metabolites produced by this strain. Manual annotation of high-resolution fragmentation mass spectra by CANOPUS classified a major molecular family as putatively new thiodiketopiperazines. However, these results were opposite to the results of ChemWalker analysis based solely on MS/MS data, assigning these metabolites as various polyketides. Thus, targeted preparative HPLC isolation focusing on the most abundant features within this major molecular family resulted in the isolation of five secondary metabolites. Their structures were elucidated based on HRMS and NMR data as four new thiodiketopiperazine derivatives, botryosulfuranols D-G ( 1 - 4 ), alongside the known botryosulfuranol A ( 5 ). Compounds 1 - 3 and 5 exhibited moderate to weak antifungal activity against different test strains, accounting for the initial antifungal activity observed for its crude extract. Our study stressed the importance of full NMR-based structure elucidation for metabolomics research.

Biofilms represent a key challenge in the treatment of microbial infections; for instance, Staphylococcus aureus causes chronic or fatal infections by forming biofilms on medical devices. Herein, the fungus Arcopilus navicularis was found to produce a novel family of PKS-NRPS metabolites that are able to disrupt preformed biofilms of S. aureus . Arcopilins A-F ( 1 - 6 ), tetramic acids, and arcopilin G ( 7 ), a 2-pyridone, were elucidated using HR-ESI-MS and one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopy. Their absolute configuration was established by the synthesis of MPTA-esters for 2 , analysis of 1 H- 1 H coupling constants, and ROESY correlations, along with comparison with the crystal structure of 7 . Arcopilin A ( 1 ) not only effectively disrupts preformed biofilms of S. aureus but also potentiates the activity of gentamicin and vancomycin up to 115- and 31-fold times, respectively. Our findings demonstrate the potential application of arcopilins for the conjugated treatment of infections caused by S. aureus with antibiotics unable to disrupt preformed biofilms.

Importance: The integration of metabolomics-based approaches into the discovery pipeline has enabled improved mining and prioritization of prolific secondary metabolite producers such as endophytic fungi. However, relying on automated untargeted analysis tools might lead to misestimation of the chemical complexity harbored in these organisms. Our study emphasizes the importance of isolation and structure elucidation of the respective metabolites in addition to deep metabolome analysis for the correct interpretation of untargeted metabolomics approaches such as molecular networking. Additionally, it encourages the further exploration of endophytic fungi from traditional medicinal plants for the discovery of natural products., Competing Interests: The authors declare no conflict of interest.

Four unprecedented polyketides named isoprenylisobenzofuran B ( 2 ), isoprenylisobenzofuran C 1 /C 2 ( 3 ), diaporisoindole F 1 /F 2 ( 4 ), and isochromophilonol A 1 /A 2 ( 7 ) were isolated from ethyl acetate extracts of the newly described endophytic fungus Diaporthe africana . Additionally, the previously reported cyclic depsipeptide eucalactam B ( 1 ) was also identified, along with the known compounds diaporisoindole A/B ( 5 ), tenellone B ( 6 ) and beauvericin ( 8 ). The taxonomic identification of the fungus was accomplished using a polyphasic approach combining multi-gene phylogenetic analysis and microscopic morphological characters. The structures 1 - 8 were determined by a detailed analysis of their spectral data, namely high-resolution electrospray ionization mass spectrometry (HR-ESIMS), 1D/2D nuclear magnetic resonance (NMR) spectroscopy, as well as electronic circular dichroism (ECD) spectra. In addition, chemical methods such as Marfey's analysis were also employed to determine the stereochemistry in compound 1 . All the compounds obtained were evaluated for antimicrobial and in vitro cytotoxic properties. Compounds 3 - 8 were active against certain fungi and Gram-positive bacteria with MIC values of 8.3 to 66.6 µg/mL. In addition, 3 - 5 displayed cytotoxic effects (22.0 ≤ IC 50 ≤ 59.2 µM) against KB3.1 and L929 cell lines, whereas compounds 6 - 8 inhibited the growth of seven mammalian cancer cell lines with IC 50 ranging from 17.7 to 49.5 µM ( 6 ), 0.9 to 12.9 µM ( 7 ) and 1.9 to 4.3 µM ( 8 )., Competing Interests: The authors declare no conflicts of interest.

During the course of our search for biologically active secondary metabolites from fungal cultures, a new oligocyclic diterpenoidal derivative, panapophenanthrin ( 1 ), was isolated from Panus strigellus . In addition, two known metabolites, panepophenanthrin ( 2 ) and dihydrohypnophilin ( 3 ), were also obtained. The chemical structures of the isolated compounds were elucidated based on extensive 1D and 2D NMR spectral analyses together with high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The absolute configuration was determined through TDDFT-ECD calculations. All of the compounds were assessed for their antimicrobial and cytotoxic activities. Compounds 1 and 3 showed moderate to weak activities in the performed antimicrobial assays, while compound 1 exhibited potent cytotoxic activity against the mammalian cell lines mouse fibroblast (L929) and human endocervical adenocarcinoma (KB3.1).