<i>De Novo</i> 3‑(Phenylcarbamoyl) Benzoate Analogues: Efficacy against Multidrug-Resistant S. aureus and Elucidation of the Biodistribution Profile

This study presents the first design, synthesis, and characterization of a novel library of carboxylate analogues of 3-(phenylcarbamoyl) benzoate (L1–L17) as potent antimicrobial agents targeting Staphylococcus aureus infections. The lead compounds L8, L13, L14, and L15 demonstrated significant activity against methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA, respectively) with MIC values of 2–8 μg/mL. Mechanistic investigations using scanning electron microscopy (SEM) and atomic force microscopy (AFM) revealed bacterial membrane disruption as the primary mode of action. Further in vitro, in silico, and in vivo analyses identified L13 and L15 as the most promising candidates. A translational study using a BALB/c mouse skin abscess model confirmed their therapeutic potential, supported by biodistribution profiling via LC/Q-TOF mass spectrometry. These findings mark a significant step toward developing novel antibiotics against S. aureus, particularly for hospital-acquired infections, offering a promising avenue in the fight against antimicrobial resistance.本研究首次完成了3-(苯基氨基甲酰)苯甲酸羧酸盐类似物库（编号L1~L17）的设计、合成与表征，该库可作为靶向金黄色葡萄球菌（Staphylococcus aureus）感染的强效抗菌剂。先导化合物L8、L13、L14及L15对耐甲氧西林金黄色葡萄球菌（methicillin-resistant S. aureus, MRSA）与耐万古霉素金黄色葡萄球菌（vancomycin-resistant S. aureus, VRSA）均表现出显著抗菌活性，最低抑菌浓度（MIC）为2~8 μg/mL。通过扫描电子显微镜（SEM）与原子力显微镜（AFM）开展的机制研究显示，破坏细菌细胞膜是该类化合物的主要作用模式。进一步的体外、计算机模拟与体内分析表明，L13与L15为最具开发潜力的候选化合物。利用BALB/c小鼠皮肤脓肿模型开展的转化研究验证了其治疗潜力，该结论得到了通过液相色谱-四极杆飞行时间串联质谱（LC/Q-TOF mass spectrometry）进行的生物分布分析的支持。本研究成果为开发针对金黄色葡萄球菌（尤其是医院获得性感染）的新型抗生素迈出了重要一步，为对抗抗菌药物耐药性提供了极具前景的研究方向。