Department of Chemistry , University of California, Irvine , Irvine , California 92697-2025 , United States.
J Am Chem Soc. 2018 Oct 31;140(43):14028-14032. doi: 10.1021/jacs.8b07709. Epub 2018 Oct 12.
This paper describes the X-ray crystallographic structure of a derivative of the antibiotic teixobactin and shows that its supramolecular assembly through the formation of antiparallel β-sheets creates binding sites for oxyanions. An active derivative of teixobactin containing lysine in place of allo-enduracididine assembles to form amyloid-like fibrils, which are observed through a thioflavin T fluorescence assay and by transmission electron microscopy. A homologue, bearing an N-methyl substituent, to attenuate fibril formation, and an iodine atom, to facilitate X-ray crystallographic phase determination, crystallizes as double helices of β-sheets that bind sulfate anions. β-Sheet dimers are key subunits of these assemblies, with the N-terminal methylammonium group of one monomer and the C-terminal macrocycle of the other monomer binding each anion. These observations suggest a working model for the mechanism of action of teixobactin, in which the antibiotic assembles and the assemblies bind lipid II and related bacterial cell wall precursors on the surface of Gram-positive bacteria.
本文描述了抗生素泰妙菌素的一种衍生物的 X 射线晶体结构，并表明其通过形成反平行 β-折叠的超分子组装为含氧阴离子创造了结合位点。含有赖氨酸代替 allo-enduracididine 的泰妙菌素活性衍生物组装形成类似淀粉样的原纤维，通过硫代黄素 T 荧光测定法和透射电子显微镜观察到这一点。一种同源物带有 N-甲基取代基以减弱原纤维的形成，以及一个碘原子以促进 X 射线晶体学相确定，结晶为β-片层的双链，结合硫酸根阴离子。β-片层二聚体是这些组装体的关键亚基，一个单体的 N-端甲基铵基团和另一个单体的 C-端大环结合每个阴离子。这些观察结果表明了泰妙菌素作用机制的工作模型，其中抗生素组装，并且组装体结合革兰氏阳性菌表面的脂质 II 和相关细菌细胞壁前体。
