Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, School of Pharmacy, Chengdu University, Chengdu, 610106, PR China.
Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, School of Pharmacy, Chengdu University, Chengdu, 610106, PR China.
Eur J Med Chem. 2024 Oct 5;276:116716. doi: 10.1016/j.ejmech.2024.116716. Epub 2024 Jul 26.
In the current study, to discover novel antibacterial agents, we designed and synthesized 72 carvacrol and thymol derivatives by biomimicking the structure and function of cationic antimicrobial peptides (AMPs). Many of the derivatives showed good antibacterial activity, and compound thy2I exhibited the most potent antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 0.5 μg/mL to 8 μg/mL. Compound thy2I could kill both gram-positive and gram-negative bacteria via a membrane-targeting mechanism of action with a low frequency of resistance. In addition, thy2I had the advantages of good membrane selectivity, low toxicity in vitro and in vivo, and good plasma stability. The in vivo activity results revealed that thy2I exhibited a positive therapeutic effect in a mouse skin abscess model induced by Staphylococcus aureus ATCC29213. After thy2I treatment (10 mg/kg), the bacterial load of the S. aureus-infected abscesses was reduced by approximately 99.65 %. Our study suggests that thy2I may serve as an antibacterial lead for further clinical evaluation.
在本研究中，为了发现新型抗菌剂，我们通过模拟阳离子抗菌肽（AMP）的结构和功能设计并合成了 72 种香芹酚和麝香草酚衍生物。许多衍生物表现出良好的抗菌活性，化合物 thy2I 表现出最强的抗菌活性，最小抑菌浓度（MIC）值在 0.5μg/mL 至 8μg/mL 之间。化合物 thy2I 可以通过靶向细胞膜的作用机制杀死革兰氏阳性菌和革兰氏阴性菌，其耐药频率较低。此外，thy2I 具有良好的膜选择性、体外和体内低毒性以及良好的血浆稳定性。体内活性结果表明，thy2I 在金黄色葡萄球菌 ATCC29213 诱导的小鼠皮肤脓肿模型中表现出积极的治疗效果。经 thy2I 治疗（10mg/kg）后，金黄色葡萄球菌感染脓肿中的细菌负荷减少了约 99.65%。我们的研究表明，thy2I 可能成为进一步临床评估的抗菌先导化合物。
