NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106, Warsaw, Poland.
Nat Commun. 2018 Sep 27;9(1):3963. doi: 10.1038/s41467-018-06314-x.
The alarming rise of antimicrobial resistance requires antibiotics with unexploited mechanisms. Ideal templates could be antibiotics that target the peptidoglycan precursor lipid II, known as the bacterial Achilles heel, at an irreplaceable pyrophosphate group. Such antibiotics would kill multidrug-resistant pathogens at nanomolecular concentrations without causing antimicrobial resistance. However, due to the challenge of studying small membrane-embedded drug-receptor complexes in native conditions, the structural correlates of the pharmaceutically relevant binding modes are unknown. Here, using advanced highly sensitive solid-state NMR setups, we present a high-resolution approach to study lipid II-binding antibiotics directly in cell membranes. On the example of nisin, the preeminent lantibiotic, we show that the native antibiotic-binding mode strongly differs from previously published structures, and we demonstrate that functional hotspots correspond to plastic drug domains that are critical for the cellular adaptability of nisin. Thereby, our approach provides a foundation for an improved understanding of powerful antibiotics.
抗菌药物耐药性的惊人增长需要具有未开发机制的抗生素。理想的模板可以是针对肽聚糖前体脂质 II 的抗生素，脂质 II 被称为细菌的阿喀琉斯之踵，位于一个不可替代的焦磷酸基团上。这种抗生素可以在毫摩尔浓度下杀死多药耐药病原体，而不会引起抗菌药物耐药性。然而，由于研究天然条件下小的膜嵌入药物受体复合物的挑战性，与药用相关的结合模式的结构相关性尚不清楚。在这里，我们使用先进的高灵敏度固态 NMR 设备，提出了一种直接在细胞膜上研究脂质 II 结合抗生素的高分辨率方法。以卓越的羊毛硫抗生素尼生素为例，我们表明天然抗生素结合模式与先前发表的结构有很大的不同，并且我们证明功能热点对应于对于尼生素的细胞适应性至关重要的可塑性药物结构域。因此，我们的方法为更好地理解强大的抗生素提供了基础。
