X‑ray Crystallographic Structure of a Teixobactin Derivative Reveals Amyloid-like Assembly

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.