State Key Laboratory for Macromolecule Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China.
State Key Laboratory for Macromolecule Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China.
Bioorg Med Chem Lett. 2024 Nov 15;113:129949. doi: 10.1016/j.bmcl.2024.129949. Epub 2024 Sep 5.
The rapid growth of bacterial resistance has created obstacles for the effective treatment with conventional antibiotics, simultaneously posing a major threat to public health. In this study, a class of novel amphipathic pyranochromene derivatives were designed and synthesized by mimicking the amphiphilic characteristics of AMPs. Bioactivity screening identified a lead compound 5a with broad-spectrum antibacterial activity against Gram-positive stains (MICs = 1-4 μg/mL) and low hemolytic toxicity (HC = 111.6 μg/mL). Additionally, compound 5a displayed rapid bactericidal action, and was unlikely to induce bacterial resistance. Mechanistic investigation further demonstrated that compound 5a was able to disrupt the transmembrane potential and increased membrane permeability of S. aureus, which in turn causes leakage of cell contents such as DNA and proteins, ultimately leading to bacterial death. These findings indicated that compound 5a is a promising lead to combat bacterial infection caused by Gram-positive bacteria.
细菌耐药性的迅速增长给常规抗生素的有效治疗带来了障碍，同时对公共健康构成了重大威胁。在这项研究中，我们通过模拟 AMPs 的两亲特性设计并合成了一类新型的两亲性吡喃并色烯衍生物。生物活性筛选发现了一个具有广谱抗革兰氏阳性菌活性的先导化合物 5a（MICs = 1-4 μg/mL），且溶血毒性低（HC = 111.6 μg/mL）。此外，化合物 5a 具有快速杀菌作用，且不易诱导细菌耐药性。机制研究进一步表明，化合物 5a 能够破坏金黄色葡萄球菌的跨膜电位并增加其细胞膜通透性，进而导致细胞内容物（如 DNA 和蛋白质）的泄漏，最终导致细菌死亡。这些发现表明，化合物 5a 是一种有前途的先导化合物，可用于对抗由革兰氏阳性菌引起的细菌感染。
