Novel Rationally Designed Lipopeptides Derived from Bacitracin: Combating Multidrug Resistance and Evading Bacitracin Resistance via Potentiated Cell Wall and Membrane Inhibitions

The escalating threat posed by multidrug-resistant bacteria underscores the urgent need for novel antibiotics. Bacitracin, with its unique undecaprenyl pyrophosphate-targeting mechanism, serves as an ideal template for structural optimization. Herein, we developed a site-selective modification strategy targeting the 7-ornithine amino group, a critical yet underexplored residue in bacitracin. This approach revitalized bacitracin’s therapeutic potential against multidrug-resistant pathogens, achieving even up to 256-fold improved activity against methicillin-, vancomycin-, and daptomycin-resistant strains while systematically establishing previously unreported SAR at this locus. The lead compound, Bac-51, incorporating an optimized trifluoromethyl biphenyl moiety, demonstrated superior in vitro potency, favorable safety/pharmacokinetic profiles, and single-dose efficacy in a lethal MRSA sepsis murine model. Mechanistic studies revealed it has a dual mode of action: enhanced peptidoglycan biosynthesis inhibition and membrane-disrupting activity, which minimized resistance development and exhibited continuous efficacy against acquired bacitracin-resistant strains. Collectively, Bac-51 represents a next-generation bacitracin analog as a promising candidate for combating multidrug-resistant Gram-positive infections.

多重耐药菌造成的威胁持续升级，凸显了研发新型抗生素的迫切需求。杆菌肽（Bacitracin）凭借其独特的靶向十一异戊烯焦磷酸（undecaprenyl pyrophosphate）的作用机制，成为结构优化的理想模板。本研究开发了一种针对7-鸟氨酸氨基的位点选择性修饰策略，该位点是杆菌肽中一个关键却尚未得到充分探索的残基。该策略重新激活了杆菌肽对抗多重耐药病原菌的治疗潜力，对甲氧西林、万古霉素和达托霉素耐药菌株的活性最高提升达256倍，同时系统构建了该位点此前未被报道的结构-活性关系（Structure-Activity Relationship，SAR）。先导化合物Bac-51引入了优化后的三氟甲基联苯基团，展现出更优异的体外活性、良好的安全性与药代动力学特性，且在致死性耐甲氧西林金黄色葡萄球菌败血症小鼠模型中表现出单剂量给药的治疗效果。机制研究揭示其具有双重作用模式：增强的肽聚糖（peptidoglycan）生物合成抑制活性与膜破坏活性，这一特性降低了耐药性的产生，并对获得性杆菌肽耐药菌株持续有效。综上，Bac-51作为下一代杆菌肽类似物，是对抗多重耐药革兰氏阳性菌感染的极具前景的候选药物。