A novel α-mangostin derivative synergistic to antibiotics against MRSA with unique mechanisms

文献类型： 外文期刊

第一作者： Ge, Rile

作者： Ge, Rile;Zhao, Haiyan;Ge, Rile;Tang, Qun;Wang, Xiaoyang;Zhang, Keyu;Ye, Wenchong;Han, Xiangan;Wang, Chunmei;Zhou, Wen;Chandarajoti, Kasemsiri;Chandarajoti, Kasemsiri;Bai, Han;Wang, Xiaoyang;Zhang, Keyu;Ye, Wenchong;Wang, Chunmei;Zhou, Wen

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关键词： alpha-MG derivatives; antibiotics; MRSA; synergistic antibacterial effects; in vitro; in vivo

期刊名称：MICROBIOLOGY SPECTRUM （ 影响因子：3.8； 五年影响因子：4.1 ）

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年卷期： 2024 年 12 卷 12 期

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收录情况： SCI

摘要： Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading cause of hospital-acquired infections, often linked to complicated treatments, increased mortality risk, and significant cost burdens. Several antibacterial agents have been developed to address MRSA resistance. In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized alpha-mangostin (alpha-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. alpha-MG-4, featuring an allyl group at C3 of the lead compound alpha-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although alpha-MG-4 alone was ineffective against MRSA2, it exhibited an optimal synergistic ratio in vitro when combined with these antibiotics. This significant synergistic antibacterial effect was further confirmed in vivo using a mouse skin abscess model. Additionally, the synergistic mechanisms revealed that alpha-MG-4 was associated with changes in membrane permeability and inhibition of the MepA and NorA genes, which encode the efflux pumps of MRSA2. alpha-MG-4 also inhibited PBP2a expression, potentially by occupying a crucial binding site in a dose-dependent manner.

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