Covering: 2014 to June 2022 The gut microbiota has attracted increasing attention from researchers due to its critical role in regulating human physiology and pathophysiology. Natural products (NPs) produced or transformed by gut microbes are key signalling mediators for a variety of physiological functions. On the other hand, NPs from ethnomedicines have also been found to generate health benefits through modulation of the gut microbiota. In this highlight, we review the most recent studies related to gut microbiota-derived NPs and bioactive NPs that regulate physiological and pathological processes via gut microbiota-associated mechanisms. We also outline the strategies for the discovery of gut microbiota-derived NPs and the methodologies of how to elucidate the crosstalk between bioactive NPs and the gut microbiota.

Methicillin-resistant Staphylococcus aureus (MRSA), a WHO high-priority pathogen that can cause great harm to living beings, is a primary cause of death from antibiotic-resistant infections. In the present study, six new compounds, including fumindoline A–C (1–3), 12β, 13β-hydroxy-asperfumigatin (4), 2-epi-tryptoquivaline F (17) and penibenzophenone E (37), and thirty-nine known ones were isolated from the marine-derived fungus Aspergillus fumigatus H22. The structures and the absolute configurations of the new compounds were unambiguously assigned by spectroscopic data, mass spectrometry (MS), electronic circular dichroism (ECD) spectroscopic analyses, quantum NMR and ECD calculations, and chemical derivatizations. Bioactivity screening indicated that nearly half of the compounds exhibit antibacterial activity, especially compounds 8 and 1 1, and 33–38 showed excellent antimicrobial activities against MRSA, with minimum inhibitory concentration (MIC) values ranging from 1.25 to 2.5 μM. In addition, compound 8 showed moderate inhibitory activity against Mycobacterium bovis (MIC: 25 μM), compound 10 showed moderate inhibitory activity against Candida albicans (MIC: 50 μM), and compound 13 showed strong inhibitory activity against the hatching of a Caenorhabditis elegans egg (IC₅₀: 2.5 μM).

Fungal natural products play a prominent role in the development of pharmaceuticalagents. Two new cyclic tetrapeptides (CTPs), westertide A (1) and B (2), with eight known compounds (3–10) were isolated from the fungus Aspergillus westerdijkiae guided by OSMAC (one strain-many compounds) and molecular networking strategies. The structures of new compounds were unambiguously determined by a combination of NMR and mass data analysis, and chemical methods. All of the isolates were evaluated for antimicrobial effects, synergistic antifungal activity, cytotoxic activity, and HDAC inhibitory activity. Compounds 1–2 showed synergistic antifungal activity against Candida albicans SC5314 with the presence of rapamycin and weak HDAC (histone deacetylase) inhibitory activity. These results indicate that molecular networking is an efficient approach for dereplication and identification of new CTPs. CTPs might be a good starting point for the development of synergistic antifungal agents.

Under the guidance of LC-MS/MS-based molecular networking, seven new verrucosidin derivatives, penicicellarusins A-G (3–9), were isolated together with three known analogues from the fungus Penicillium cellarum. The structures of the new compounds were determined by a combination of NMR, mass and electronic circular dichroism spectral data analysis. The absolute configuration of penicyrone A (10) was corrected based on X-ray diffraction analyses. Bioactivity screening indicated that compounds 1, 2, and 4 showed much stronger promising hypoglycemic activity than the positive drug (rosiglitazone) in the range of 25–100 μM, which represents a potential new class of hypoglycemic agents. Preliminary structure-activity relationship analysis indicates that the formation of epoxy ring on C₆-C₇ in the structures is important for the glucose uptake-stimulating activity. The gene cluster for the biosynthesis of 1–12 is identified by sequencing the genome of P. cellarum and similarity analysis with the gene cluster of verrucosidins in P. polonicum.

Ganoderma lucidum methyl ganoderate E (MGE) improves healthspan and extends lifespan through the insulin/IGF-1 pathway, modulating neuroactive signaling and ubiquitin-mediated proteolysis.