Membrane-Targeting Amphiphilic Honokiol Derivatives Containing an Oxazole Moiety as Potential Antibacterials against Methicillin-Resistant Staphylococcus aureus,Journal of Medicinal Chemistry

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Membrane-Targeting Amphiphilic Honokiol Derivatives Containing an Oxazole Moiety as Potential Antibacterials against Methicillin-Resistant Staphylococcus aureus
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-11 , DOI: 10.1021/acs.jmedchem.4c01860
Ruige Yang _{1,

2} , Liping Cui ₂ , Shengnan Xu ₁ , Yan Zhong ₁ , Ting Xu ₁ , Jifeng Liu ₂ , Zhenwei Lan ₃ , Shangshang Qin ₂ , Yong Guo _{1,

2}

Affiliation

Infections with methicillin-resistant Staphylococcus aureus (MRSA) are becoming increasingly serious, making the development of novel antimicrobials urgent. Here, we synthesized some amphiphilic honokiol derivatives bearing an oxazole moiety and investigated their antibacterial and hemolytic activities. Bioactivity evaluation showed that E17 possessed significant in vitro antibacterial activity against S. aureus and MRSA, along with low hemolytic activity. Moreover, E17 exhibited rapid bactericidal properties and was not susceptible to resistance. Mechanistic studies indicated that E17 interacts with phosphatidylglycerol and cardiolipin of bacterial cell membranes, leading to changes in cell membrane permeability and polarization, increased intracellular ROS, and leakage of DNA and proteins, thus accelerating bacterial death. Transcriptome analysis further demonstrated that E17 has membrane-targeting effects, affecting the expression of genes related to cell membranes and ABC transporter proteins. Notably, in vivo activity showed that E17 has prominent anti-MRSA efficacy, comparable to vancomycin, and is expected to be a new anti-MRSA drug candidate.

中文翻译：

含有恶唑部分的膜靶向两亲性和厚朴酚衍生物作为抗甲氧西林金黄色葡萄球菌的潜在抗菌剂

耐甲氧西林金黄色葡萄球菌（MRSA）的感染变得越来越严重，使得新型抗菌药物的开发刻不容缓。在这里，我们合成了一些带有恶唑部分的两亲性和厚朴酚衍生物，并研究了它们的抗菌和溶血活性。生物活性评价表明， E17对金黄色葡萄球菌和MRSA具有显着的体外抗菌活性，并且具有较低的溶血活性。此外， E17表现出快速杀菌特性并且不易产生耐药性。机理研究表明， E17与细菌细胞膜的磷脂酰甘油和心磷脂相互作用，导致细胞膜通透性和极化发生变化，细胞内ROS增加，DNA和蛋白质渗漏，从而加速细菌死亡。转录组分析进一步证明E17具有膜靶向作用，影响细胞膜和ABC转运蛋白相关基因的表达。值得注意的是，体内活性表明E17具有显着的抗MRSA功效，可与万古霉素相媲美，有望成为新的抗MRSA候选药物。

更新日期：2024-09-11

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