Bacterial strains used in the current study.

There has been a substantial gap between drying antibiotic pipeline and ongoing antibiotic resistance crisis, necessitating approaches to revitalize existing antimicrobials to meet unmet clinical demand for viable treatments. Herein, a lignan compound, magnolol, was identified that profoundly potentiates colistin (CS) to eradicate Gram negative bacteria and curb the development of resistance under host-mimicking condition. The mechanistic study showed that magnolol is able to disrupt PmrA/B two component signaling by dissociating the PmrA regulator protein from its cognate DNA including eptA and arnT. This action blocks the PmrA/B-dependent protective modifications of lipopolysaccharide (LPS) to reduce the net charges of bacterial membrane, thereaby facilitating its electrostatic interaction with CS. MAG-facilitated enhancement of CS binding promotes the formation of toroidal pores in the bacterial membrane, which in turn triggers rapid bacterial death by inducing lethal cytoplasmic contents leakage. In sum, this work not only illustrates the great potential of untapped phytoconstitutes such as magnolol in confronting antibiotic resistance but also reveals that silencing PmrA/B signaling as a favorable strategy to potentiate CS activity in vivo.当前日渐枯竭的抗生素研发管线与持续蔓延的抗生素耐药性危机之间存在显著鸿沟，亟需开发可活化现有抗菌药物的新策略，以满足临床对有效治疗手段尚未被满足的需求。本研究鉴定出一种木脂素类化合物——厚朴酚（magnolol），其可在宿主模拟环境中显著增强多粘菌素E（colistin, CS）的活性，彻底清除革兰氏阴性菌并抑制耐药性的产生。机制研究表明，厚朴酚可通过将PmrA调节蛋白从其同源DNA（包括eptA与arnT基因）上解离，从而阻断PmrA/B双组分信号通路。该作用可抑制依赖PmrA/B的脂多糖（LPS）保护性修饰，降低细菌细胞膜的净电荷，进而促进其与多粘菌素E的静电相互作用。厚朴酚介导的多粘菌素E结合增强可促进细菌细胞膜形成环形孔道，最终通过诱导致命性胞质内容物渗漏快速杀灭细菌。综上，本研究不仅揭示了厚朴酚这类未被充分挖掘的植物活性成分在对抗抗生素耐药性方面的巨大潜力，同时证实了抑制PmrA/B信号通路是一种可在体内增强多粘菌素E活性的有效策略。