The increase in antibiotic resistance has made it particularly urgent to develop new antibiotics with novel antibacterial mechanisms. Inhibition of bacterial cell division by disrupting filamentous temperature-sensitive mutant Z (FtsZ) function is an effective and promising approach. A series of novel fascaplysin derivatives with tunable hydrophobicity were designed and synthesized here. The in vitro bioactivity assessment revealed that these compounds could inhibit the tested Gram-positive bacteria including methicillin-resistant S. aureus (MRSA) (MIC = 0.049–25 μg/mL), B. subtilis (MIC = 0.024–12.5 μg/mL) and S. pneumoniae (MIC = 0.049–50 μg/mL). Among them, compounds B3 (MIC = 0.098 μg/mL), B6 (MIC = 0.098 μg/mL), B8 (MIC = 0.049 μg/mL) and B16 (MIC = 0.098 μg/mL) showed the best bactericidal activities against MRSA and no significant tendency to trigger bacterial resistance as well as rapid bactericidal properties. The cell surface integrity of bacteria was significantly disrupted by hydrophobic tails of fascaplysin derivatives. Further studies revealed that these highly active amphiphilic compounds showed low hemolytic activity and cytotoxicity to mammalian cells. Preliminary mechanistic exploration suggests that B3, B6, B8 and B16 are potent FtsZ inhibitors to promote FtsZ polymerization and inhibit GTPase activity of FtsZ, leading to the death of bacterial cells by inhibiting bacterial division. Molecular docking simulations and structure-activity relationship (SAR) study reveal that appropriate increase in the hydrophobicity of fascaplysin derivatives and the addition of additional hydrogen bonds facilitated their binding to FtsZ proteins. These amphiphilic fascaplysin derivatives could serve as a novel class of FtsZ inhibitors, which not only gives new prospects for the application of compounds containing this skeleton but also provides new ideas for the discovery of new antibiotics.

抗生素耐药性的增加使得开发具有新抗菌机制的新型抗生素变得尤为迫切。通过破坏丝状温度敏感突变体 Z (FtsZ) 功能来抑制细菌细胞分裂是一种有效且有前途的方法。这里设计并合成了一系列具有可调疏水性的新型fascaplysin衍生物。体外生物活性评估表明，这些化合物可以抑制测试的革兰氏阳性菌，包括耐甲氧西林金黄色葡萄球菌(MRSA) (MIC = 0.049–25 μg/mL)、枯草芽孢杆菌( MIC = 0.024–12.5 μg/mL) ) 和肺炎链球菌(MIC = 0.049–50 μg/mL)。其中，化合物B3(MIC = 0.098 μg/mL)、B6 (MIC = 0.098 μg/mL)、B8 (MIC = 0.049 μg/mL) 和B16 (MIC = 0.098 μg/mL)对 MRSA表现出最好的杀菌活性，并且没有显着的倾向触发细菌耐药性以及快速杀菌特性。fascaplysin 衍生物的疏水性尾巴显着破坏了细菌的细胞表面完整性。进一步的研究表明，这些高活性两亲化合物对哺乳动物细胞表现出低溶血活性和细胞毒性。初步的机理探索表明B3、B6、B8和B16是有效的 FtsZ 抑制剂，可促进 FtsZ 聚合并抑制 FtsZ 的 GTPase 活性，通过抑制细菌分裂导致细菌细胞死亡。分子对接模拟和结构-活性关系 (SAR) 研究表明，适当增加 fascaplysin 衍生物的疏水性和添加额外的氢键有助于它们与 FtsZ 蛋白的结合。这些两亲性fascaplysin衍生物可以作为一类新型的FtsZ抑制剂，不仅为含有该骨架的化合物的应用提供了新的前景，也为新抗生素的发现提供了新的思路。