The rise of antimicrobial resistance poses a substantial threat to our health system, and, hence, development of drugs against novel targets is urgently needed. The natural peptide thanatin kills Gram-negative bacteria by targeting proteins of the lipopolysaccharide transport (Lpt) machinery. Using the thanatin scaffold together with phenotypic medicinal chemistry, structural data, and a target-focused approach, we developed antimicrobial peptides with drug-like properties. They exhibit potent activity against Enterobacteriaceae both in vitro and in vivo while eliciting low frequencies of resistance. We show that the peptides bind LptA of both wild-type and thanatin-resistant Escherichia coli and Klebsiella pneumoniae strains with low-nanomolar affinities. Mode of action studies revealed that the antimicrobial activity involves the specific disruption of the Lpt periplasmic protein bridge.

中文翻译：

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拟肽抗生素破坏耐药肠杆菌科细菌的脂多糖转运桥


抗菌素耐药性的上升对我们的卫生系统构成了重大威胁，因此迫切需要开发针对新靶点的药物。天然肽 Thanatin 通过靶向脂多糖转运 (Lpt) 机制的蛋白质来杀死革兰氏阴性细菌。利用thanatin支架与表型药物化学、结构数据和以靶点为中心的方法，我们开发了具有药物样特性的抗菌肽。它们在体外和体内均表现出针对肠杆菌科的有效活性，同时引起低频率的耐药性。我们证明这些肽可以结合野生型和抗塔纳汀的 LptA大肠杆菌和肺炎克雷伯菌具有低纳摩尔亲和力的菌株。作用方式研究表明，抗菌活性涉及 Lpt 周质蛋白桥的特异性破坏。