Affiliated Qingyuan Hospital, Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, State Key Laboratory of Respiratory Disease, and School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Affiliated Qingyuan Hospital, Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, State Key Laboratory of Respiratory Disease, and School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Eur J Med Chem. 2024 Aug 5;274:116544. doi: 10.1016/j.ejmech.2024.116544. Epub 2024 May 31.
Antibiotic resistance is becoming increasingly severe. The development of small molecular antimicrobial peptides is regarded as a promising design strategy for antibiotics. Here, a series of bisphenol derivatives with amphiphilic structures were designed and synthesized as antibacterial agents by imitating the design strategy of antimicrobial peptides. After a series of structural optimizations, lead compound 43 was identified, which exhibited excellent antibacterial activity against Gram-positive bacterial strains (MICs = 0.78-1.56 μg/mL), poor hemolytic activity (HC > 200 μg/mL), and low cytotoxicity (CC > 100 μg/mL). Further biological evaluation results indicated that 43 exerted antibacterial effects by directly destroying bacterial cell membranes and displayed rapid bactericidal properties (within 0.5-1 h), leading to a very low probability of drug resistance. Moreover, in a murine model of corneal infection, 43 exhibited a strong in vivo antibacterial efficacy. These findings indicate that 43 is a promising candidate compound for the treatment of bacterial infections.
抗生素耐药性日益严重。小分子抗菌肽的开发被认为是抗生素设计的一种有前途的策略。在这里，通过模仿抗菌肽的设计策略，设计并合成了一系列具有两亲结构的双酚衍生物作为抗菌剂。经过一系列的结构优化，确定了先导化合物 43，它对革兰氏阳性菌菌株表现出优异的抗菌活性（MICs=0.78-1.56μg/mL），溶血活性差（HC>200μg/mL），细胞毒性低（CC>100μg/mL）。进一步的生物学评价结果表明，43 通过直接破坏细菌细胞膜发挥抗菌作用，具有快速杀菌特性（在 0.5-1 小时内），因此耐药性的可能性非常低。此外，在角膜感染的小鼠模型中，43 表现出很强的体内抗菌功效。这些发现表明 43 是一种有前途的治疗细菌感染的候选化合物。
