Antimicrobial resistance is a leading cause of mortality, calling for the development of new antibiotics. The fungal antibiotic plectasin is a eukaryotic host defence peptide that blocks bacterial cell wall synthesis. Here, using a combination of solid-state nuclear magnetic resonance, atomic force microscopy and activity assays, we show that plectasin uses a calcium-sensitive supramolecular killing mechanism. Efficient and selective binding of the target lipid II, a cell wall precursor with an irreplaceable pyrophosphate, is achieved by the oligomerization of plectasin into dense supra-structures that only form on bacterial membranes that comprise lipid II. Oligomerization and target binding of plectasin are interdependent and are enhanced by the coordination of calcium ions to plectasin’s prominent anionic patch, causing allosteric changes that markedly improve the activity of the antibiotic. Structural knowledge of how host defence peptides impair cell wall synthesis will likely enable the development of superior drug candidates.

抗生素耐药性是导致死亡的主要原因，需要开发新的抗生素。真菌抗生素菌丝酶是一种真核宿主防御肽，可阻止细菌细胞壁的合成。在这里，我们结合固态核磁共振、原子力显微镜和活性测定，证明 plectasin 使用钙敏感的超分子杀伤机制。通过将 plectasin 寡聚成仅在包含脂质 II 的细菌膜上形成的致密超结构，可以实现目标脂质 II（一种具有不可替代的焦磷酸盐的细胞壁前体）的有效和选择性结合。菌菌素的寡聚化和靶标结合是相互依赖的，并且通过钙离子与菌菌素突出的阴离子斑块的协调而增强，引起变构变化，从而显着提高抗生素的活性。关于宿主防御肽如何损害细胞壁合成的结构知识可能有助于开发优质候选药物。