研究人员利用固态核磁共振、显微镜、体内检测和分子动力学模拟的结合，在原子水平上揭示了teixobactin的机制。teixobactin独特的enduracididine C端基团与脂质II的焦磷酸-糖基特异性结合，而N端则与另一个脂质II分子的焦磷酸协调。这种配置有利于形成一个与目标结合的β-片状的teixobactins，形成一个超分子的纤维状结构。与保守的焦磷酸-糖分子的特异性结合，说明了对teixobactin缺乏抗性。该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显示，该超分子结构取代了磷脂，使膜变薄。集中在超分子结构内的脂质II的长疏水性尾巴显然有助于膜的破坏。teixobactin劫持了脂质II来帮助破坏膜。已知的膜作用抗生素也会损害人体细胞，产生不良的副作用。teixobactin只破坏含有脂质II的膜，而脂质II在真核生物中是缺乏的，从而优雅地解决了毒性问题。针对细胞壁合成和细胞质膜的双管齐下作用产生了一种针对细菌细胞包膜的高效化合物。对teixobactin机制的结构知识将使人们能够合理地设计改进的候选药物。
据悉，人们需要使用新型机制的抗生素来对抗抗菌素耐药性。teixobactin代表了一类新的抗生素，具有独特的化学支架且缺乏可检测的抗性。teixobactin的靶标是脂质II，一种肽聚糖的前体。
附：英文原文
Title: Teixobactin kills bacteria by a two-pronged attack on the cell envelope
Author: Shukla, Rhythm, Lavore, Francesca, Maity, Sourav, Derks, Maik G. N., Jones, Chelsea R., Vermeulen, Bram J. A., Melcrov, Adla, Morris, Michael A., Becker, Lea Marie, Wang, Xiaoqi, Kumar, Raj, Medeiros-Silva, Joo, van Beekveld, Roy A. M., Bonvin, Alexandre M. J. J., Lorent, Joseph H., Lelli, Moreno, Nowick, James S., MacGillavry, Harold D., Peoples, Aaron J., Spoering, Amy L., Ling, Losee L., Hughes, Dallas E., Roos, Wouter H., Breukink, Eefjan, Lewis, Kim, Weingarth, Markus
Issue&Volume: 2022-08-03
Abstract: Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1,2,3. 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.
DOI: 10.1038/s41586-022-05019-y
Source: https://www.nature.com/articles/s41586-022-05019-y
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
