The Fifth Affiliated Hospital & Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
The Fifth Affiliated Hospital & Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Eur J Med Chem. 2024 Feb 15;266:116149. doi: 10.1016/j.ejmech.2024.116149. Epub 2024 Jan 14.
The emergence of antibiotic resistance has brought a significant burden to public health. Here, we designed and synthesized a series of cannabidiol derivatives by biomimicking the structure and function of cationic antibacterial peptides. This is the first report on the design of cannabidiol derivatives as broad-spectrum antibacterial agents. Through the structure-activity relationship (SAR) study, we found a lead compound 23 that killed both Gram-negative and Gram-positive bacteria via a membrane-targeting mechanism of action with low resistance frequencies. Compound 23 also exhibited very weak hemolytic activity, low toxicity toward mammalian cells, and rapid bactericidal properties. To further validate the membrane action mechanism of compound 23, we performed transcriptomic analysis using RNA-seq, which revealed that treatment with compound 23 altered many cell wall/membrane/envelope biogenesis-related genes in Gram-positive and Gram-negative bacteria. More importantly, compound 23 showed potent in vivo antibacterial efficacy in murine corneal infection models caused by Staphylococcus aureus or Pseudomonas aeruginosa. These findings would provide a new design idea for the discovery of novel broad-spectrum antibacterial agents to overcome the antibiotic resistance crisis.
抗生素耐药性的出现给公共卫生带来了重大负担。在这里，我们通过模拟阳离子抗菌肽的结构和功能设计并合成了一系列大麻二酚衍生物。这是首次将大麻二酚衍生物设计为广谱抗菌剂的报道。通过构效关系（SAR）研究，我们发现先导化合物 23 通过靶向作用于细胞膜的作用机制，对革兰氏阴性菌和革兰氏阳性菌均具有杀菌作用，且耐药频率较低。化合物 23 还表现出极弱的溶血活性、对哺乳动物细胞的低毒性和快速杀菌特性。为了进一步验证化合物 23 的膜作用机制，我们使用 RNA-seq 进行了转录组分析，结果表明，化合物 23 处理可改变革兰氏阳性菌和革兰氏阴性菌中许多与细胞壁/膜/包膜生物发生相关的基因。更重要的是，化合物 23 在金黄色葡萄球菌或铜绿假单胞菌引起的小鼠角膜感染模型中表现出强大的体内抗菌功效。这些发现为发现新型广谱抗菌剂以克服抗生素耐药性危机提供了新的设计思路。
