School of Pharmaceutical Sciences, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China.
Pingyuan Laboratory (Zhengzhou University), Zhengzhou 450001, China.
J Med Chem. 2024 Oct 24;67(20):18576-18592. doi: 10.1021/acs.jmedchem.4c01935. Epub 2024 Oct 8.
Encouraged by the significantly different toxicities and antibacterial activities of diverse linkers, such as alkyl and aromatic nuclei linkers, and the unique structure of phloroglucinol, we synthesized a series of tris-quaternary ammonium salt (tris-QAS) antibacterial peptide mimics based on the marketed drug phloroglucinol. Among them, displayed excellent activity against (MIC = 0.5 μg/mL) and high selectivity (SI > 2560). Surprisingly, the cytotoxicity of (CC = 152.7 μg/mL) was dramatically better than those of alkyl QAS and hydroquinone QAS . Additionally, possessed rapid bactericidal capability, was not prone to inducing bacterial resistance, and also exhibited excellent activity against biofilms and persistent bacteria. Mechanistic research and transcriptome analysis revealed that can interfere with the normal metabolism of bacterial cells, and it can specifically bind with phosphatidylglycerol to destroy the cell membrane. Importantly, exhibited potent antibacterial activity in a mouse subcutaneous methicillin-resistant (MRSA) infection model.
受不同连接物（如烷基和芳核连接物）和间苯三酚独特结构所表现出的显著不同毒性和抗菌活性的鼓舞，我们基于市售药物间苯三酚合成了一系列三季铵盐（tris-QAS）抗菌肽模拟物。其中，化合物 表现出对金黄色葡萄球菌（MIC = 0.5 μg/mL）的优异活性和高选择性（SI > 2560）。令人惊讶的是，化合物 的细胞毒性（CC = 152.7 μg/mL）明显优于烷基 QAS 和对苯二酚 QAS 。此外，化合物 具有快速杀菌能力，不易诱导细菌耐药性，并且对生物膜和持久细菌也表现出优异的活性。机制研究和转录组分析表明，化合物 可以干扰细菌细胞的正常代谢，并且可以特异性地与磷脂酰甘油结合以破坏细胞膜。重要的是，化合物 在耐甲氧西林金黄色葡萄球菌（MRSA）感染的小鼠皮下模型中表现出很强的抗菌活性。
