7α-Hydroxypaxilline, a Natural Product Isolated from Mangrove Endophytic Fungi, Inhibits Protein Translation in Vibrio alginolyticus

Vibrio alginolyticus, a prevalent marine Gram-negative pathogenic bacterium, can cause vibriosis in aquaculture and pose potential threats to human health. The excessive abuse of antibiotics has aggravated the multidrug resistance of bacteria, driving researchers to explore natural antibacterial substances from mangrove endophytic fungi. In this study, four known indole-diterpenoids, 7α-hydroxypaxilline (1), paspaline (2), paspalinine (3), 4a-demethylpaspaline-4a-carboxylic acid (4), were isolated the marine-derived fungus Penicillium janthinellum D131. Among them, compound 1 exhibited superior inhibitory activity against Vibrio alginolyticus, with a minimum inhibitory concentration (MIC) of 0.781 μg/mL, which was superior to chloramphenicol (1.56 μg/mL). A series of phenotypic experiments confirmed the potent bactericidal activity of this compound. The results of multi-omics analysis and Western blot assays demonstrated that the compound disrupts the 50S ribosome-mediated translation process in bacteria. Molecular docking analysis and kinetic simulation were further performed to identify the target site, and the results revealed that the compound interacts with 23S ribosomal RNA (23S rRNA). In vitro translation assays further verified that the compound blocks bacterial protein synthesis by targeting 23S rRNA. This study reports the excellent anti-vibrio activity of 1, which is superior to chloramphenicol, and clarifies its ribosome-targeting mechanism of action. These findings provide a theoretical basis for the research and development of novel antibacterial drugs for aquaculture and broaden the potential applications of lead compounds.