A Dual-Mechanism Luminescent Antibiotic for Bacterial Infection Identification and Eradication

Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover antibacterial agents. Herein, we design and synthesize a compound of TPA2PyBu that kills both Gram-negative and Gram-positive bacteria with an undetectably low drug resistance. Comprehensive analyses reveal that the antimicrobial activity of TPA2PyBu proceeds via a unique dual mechanism by damaging bacterial membrane integrity and inducing DNA aggregation. TPA2PyBu could provide imaging specificity that differentiates bacterial infection from inflammation and cancer. Importantly, high in vivo treatment efficacy of TPA2PyBu was achieved in methicillin-resistant S. aureus infection mouse models. This promising antimicrobial agent suggests that combining multiple mechanisms of action into a single molecule can be an effective approach to address challenging bacterial infections. Overall design: The RNA-seq profiling of Staphylococcus aureus was conducted to analyze the gene expression patterns before and after treatment with the compound TPA2PyBu.

鉴于耐药细菌（antibiotic-resistant bacteria）的快速涌现，开发抗菌制剂（antibacterial agents）的需求日益迫切。本研究中，我们设计并合成了化合物TPA2PyBu，其可同时杀灭革兰氏阴性菌（Gram-negative bacteria）与革兰氏阳性菌（Gram-positive bacteria），且耐药性低至无法检出。全面机制分析显示，TPA2PyBu的抗菌活性通过独特的双重作用途径实现：破坏细菌细胞膜完整性并诱导DNA聚集。TPA2PyBu具备成像特异性，可有效区分细菌感染与炎症及癌症。尤为关键的是，在耐甲氧西林金黄色葡萄球菌（methicillin-resistant S. aureus）感染小鼠模型中，TPA2PyBu展现出了优异的体内治疗效果。这款极具开发潜力的抗菌制剂表明，将多种作用机制整合至单一分子中，可成为应对难治性细菌感染的有效策略。整体实验设计：针对金黄色葡萄球菌（Staphylococcus aureus）开展RNA测序（RNA-seq）谱分析，以解析该化合物TPA2PyBu处理前后的基因表达模式。