The emergence of multidrug resistance bacteria poses a great health theat. Therefore, it is a crucial demand to obtain new antibacterial drugs. Antimicrobial peptides (AMPs) have the characteristics of wide antimicrobial spectrum and lower drug resistance, hence, it is hopeful to substitute for classical antibiotics. In this study, two classic methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), were used to analyze the structural feature of AMPs against Staphylococcus aureus or Escherichia coli, respectively. Subsequently, the models established by three-dimensional quantitative structure–activity relationships (3D-QSAR) (for S. aureus, CoMFA: Q² = 0.512, R² = 0.943, F = 59.916; CoMSIA: Q² = 0.645, R² = 0.993, F = 339.242; for E. Coli, CoMFA: Q² = 0.507, R² = 0.913, F = 66.862; CoMSIA: Q² = 0.573, R² = 0.966, F = 96.84) have good predictability and stability was constructed. Seven novel small AMPs were designed and synthesized based on the theoretical model. The novel AMPs showed potent antibacterial activity against S. aureus and E. coli while causing low host toxicity. This study provides a potential therapeutic option using 3D-QSAR models guiding the design and modification of novel AMPs, to address the prevalent infections caused by MDR bacterial.

多药耐药细菌的出现给健康带来了巨大的压力。因此，获得新的抗菌药物是至关重要的需求。抗菌肽（AMPs）具有抗菌谱广、耐药性低的特点，有望替代经典抗生素。本研究采用比较分子场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)两种经典方法分别分析AMPs对金黄色葡萄球菌或大肠杆菌的结构特征。随后，通过三维定量构效关系（3D-QSAR）建立的模型（对于金黄色葡萄球菌，CoMFA：Q ²  = 0.512，R ²  = 0.943，F  = 59.916；CoMSIA：Q ²  = 0.645，R ²  = 0.993，F  = 339.242；对于大肠杆菌，CoMFA：Q ²  = 0.507，R ²  = 0.913，F  = 66.862；CoMSIA：Q ²  = 0.573，R ²  = 0.966，F  = 96.84）具有良好的可预测性和稳定性。基于理论模型设计并合成了七种新型小AMP。新型 AMP 对金黄色葡萄球菌和大肠杆菌显示出有效的抗菌活性同时造成低宿主毒性。这项研究提供了一种潜在的治疗选择，使用 3D-QSAR 模型指导新型 AMP 的设计和修改，以解决由 MDR 细菌引起的普遍感染。