Microbial infections and the emergence of antibiotic resistance have become major global health concerns. The continuous search for structurally unique and pharmacologically active compounds derived from natural sources is crucial for the development of new antimicrobial agents. Marine-derived fungi represent a prolific source of chemically diverse natural products with great potential for the discovery of novel antibiotics. In this study, four new naphtho-pyrone dimers, curvupyrones A–D (1–4), six new xanthone dimer derivatives, curvupyrones E–J (5–10), and three known analogs (11–13) were isolated from the mangrove endophytic fungus Curvularia sp. QQYZ-4 under bioactivity-directed guidance and heteronuclear single quantum coherence (HSQC)-based DeepSAT. The planar structures of new compounds 1–10 were elucidated using high-resolution electrospray ionization mass spectrometry (HRESIMS) and 1D/2D NMR. Compounds 1–10 possess complex axial chirality and stereochemical configurations, and their absolute configurations were determined by comprehensive analysis combining energy barrier calculations, nuclear Overhauser effect spectroscopy (NOESY) analysis, Cotton effects, DP4⁺ analysis, and ECD calculations. Notably, 9–12 exhibit significant antimicrobial activity against Escherichia coli (E. coli), Salmonella typhimurium (S. typhimurium), Methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans (C. albicans), with MICs ranging from 2 to 8 μg/mL. Furthermore, scanning electron microscopy (SEM) revealed that compound 9 disrupts the structural integrity of E. coli and S. typhimurium. This study not only enriches the chemical diversity of naphtho-pyrone dimers and xanthone dimer derivatives but also provides a chemical basis for research and development targeting antimicrobial agents.
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