Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance^1,2,3. Teixobactin⁴ represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan⁵. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin⁴. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.

需要使用新机制的抗生素来对抗抗菌素耐药性^1,2,3。Teixobactin ⁴代表了一类新的抗生素，具有独特的化学支架并且缺乏可检测的耐药性。^{Teixobactin 靶向脂质 II，肽聚糖5}的前体. 在这里，我们结合使用固态核磁共振、显微镜、体内分析和分子动力学模拟，在原子水平上揭示了 teixobactin 的机制。teixobactin 独特的 enduracididine C 末端头基特异性结合脂质 II 的焦磷酸糖部分，而 N 末端协调另一个脂质 II 分子的焦磷酸盐。这种配置有利于形成与靶标结合的 teixobactins β-折叠，从而产生超分子纤维状结构。与保守的焦磷酸糖部分的特异性结合导致对 teixobactin ^{4缺乏抗性}. 超分子结构损害了膜的完整性。原子力显微镜和分子动力学模拟表明，超分子结构取代了磷脂，使膜变薄。脂质 II 的长疏水尾集中在超分子结构内显然有助于膜破裂。Teixobactin 劫持脂质 II 以帮助破坏膜。已知的膜作用抗生素也会损害人体细胞，产生不良副作用。Teixobactin 仅损害含有真核生物中不存在的脂质 II 的膜，优雅地解决了毒性问题。对细胞壁合成和细胞质膜的双重作用产生了一种针对细菌细胞包膜的高效化合物。