| Sumario: | The pericarp of Garcinia mangostana (L.) has been traditionally used in Southeast Asia and South China to alleviate diarrhea, regulate gastrointestinal functions, and promote wound healing. It is rich in xanthones, which exhibit significant antimicrobial activity. However, current research on the antimicrobial properties of mangosteen pericarp has primarily concentrated on the antibacterial effects of the xanthone compound α-mangostin, while studies on the antifungal activities of xanthones remain relatively limited. The current study aimed to extract pure compounds from mangosteen pericarp and conducted antifungal activity screening against Cryptococcus neoformans , along with an analysis of the antifungal potential and related mechanisms of action of the most potent antifungal compound. The chemical constituents of G. mangostana pericarp were isolated and identified by phytochemical study and spectroscopic data. The antifungal potential of γ-mangostin was analyzed through minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) tests, structure-activity relationship (SAR) analysis, growth curves, time-kill curves, electron microscopy, biofilm eradication and capsule formation inhibition capacity, as well as a Caenorhabditis elegans infection model treatment. Its antifungal mechanism was investigated via transcriptomic and metabolomic analyses, along with corresponding validation experiments. A total of 33 monomeric compounds were isolated from the mangosteen pericarp extract, primarily xanthone derivatives. Among them, γ-mangostin exhibited the strongest antifungal activity, with MIC and MFC values of 4 μM and 16 μM, respectively. Growth curve, time-kill kinetics, and electron microscopy experiments demonstrated that γ-mangostin exerted significant and sustained antifungal effects within 24 h. At a concentration of 4 μM, γ-mangostin significantly eradicated biofilms and inhibited capsule formation. In a C. elegans infection model, 4 μM γ-mangostin showed notable therapeutic efficacy. Furthermore, γ-mangostin displayed hemolytic activity comparable to the commercial antibiotics fluconazole and amphotericin B at concentrations up to 64 μM, with no adverse effects on nematode lifespan. Transcriptomic and metabolomic analyses revealed that γ-mangostin suppressed the ribosome biogenesis signaling pathway. qPCR analysis indicated that γ-mangostin downregulated key genes (NMD3 , NOB1 , NAT10 , and NHP2) in the ribosome biogenesis pathway. Protein content assays further confirmed that γ-mangostin significantly reduced protein accumulation in C. neoformans. γ-mangostin holds potential application value in the treatment of infections caused by C. neoformans. [Display omitted]
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