article · Antibiotics
Enterococcus faecalis causes severe infections driven by diverse virulence factors. Two secondary metabolites isolated from the plant Cycas media, ginkgetin and sotetsuflavone, demonstrate antibacterial and antivirulence properties against this pathogen. Computational modelling shows both compounds bind key virulence proteins, with sotetsuflavone displaying stronger affinity and lower minimum inhibitory concentrations than ginkgetin. Laboratory tests reveal that sotetsuflavone distorts bacterial cell structure and impedes biofilm formation without causing significant membrane depolarisation. In a systemic infection animal model, treatment with sotetsuflavone raised survival rates and reduced inflammation across the liver and spleen. The compound also improved liver function markers and suppressed critical inflammatory cytokines, including tumour necrosis factor-alpha and interleukins. These combined findings present sotetsuflavone as a viable candidate for further therapeutic development against difficult bacterial infections.
Enterococcus faecalis can cause serious, persistent infections by establishing protective biofilms and releasing damaging virulence factors. Identifying plant-derived compounds that simultaneously weaken bacterial structure, block biofilm growth, and reduce tissue-damaging inflammation offers new avenues for treating complex bacterial conditions that resist standard care.
This work could inform the development of novel antibacterial or antivirulence therapeutics targeting Enterococcus faecalis. Potential users include pharmaceutical developers and drug discovery programmes seeking alternatives to conventional antibiotics. The research remains at an early stage, having demonstrated efficacy in computational, in vitro, and initial animal infection models, requiring further preclinical and clinical trials before any practical application.
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Enterococcus species possess many virulence factors that have an essential role in exacerbating the infections caused by them. The current study aimed to evaluate the effect of the secondary metabolites ginkgetin (GINK) and sotetsuflavone (SOTE), isolated from Cycas media R. Br dichloromethane fraction, on Enterococcus faecalis (E. faecalis) isolates for the first time. The antibacterial and antivirulence activities of the isolated compounds were investigated using docking studies and in vitro by determination of the minimum inhibitory concentrations (MICs). Additionally, flow cytometry and scanning electron microscope (SEM) were utilized to assess the effect of SOTE on the tested bacteria. Moreover, crystal violet assay and qRT-PCR were used to test the effect of SOTE on the biofilm-forming ability of E. faecalis isolates. In addition, a systemic infection model was utilized in vivo to investigate the antibacterial activity of SOTE. We found that both GINK and SOTE showed a good affinity for the five proteins enrolled in the virulence of E. faecalis, with SOTE being the highest, suggesting the possible mechanisms for the antivirulence activity of both ligands. In addition, SOTE exhibited a higher antibacterial activity than GINK, as the values of the MICs of SOTE were lower than those of GINK. Thus, we performed the in vitro and in vivo assays on SOTE. However, they did not exhibit any significant variations (p > 0.05) in the membrane depolarization of E. faecalis isolates. Moreover, as evaluated by SEM, SOTE caused distortion and deformation in the treated cells. Regarding its impact on the biofilm formation, it inhibited the biofilm-forming ability of the tested isolates, as determined by crystal violet assay and qRT-PCR. The in vivo experiment revealed that SOTE resulted in a reduction of the inflammation of the liver and spleen with an increase in the survival rate. SOTE also improved the liver-function tests and decreased tumor necrosis factor-alpha using immunostaining and the inflammation markers, interleukins (IL-1β and IL-6), using ELISA. Thus, we can conclude that SOTE could be a promising compound that should be investigated in future preclinical and clinical studies.
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DOI: 10.3390/antibiotics11080993
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