Abstract
The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance. The difficult synthesis and unfavourable solubility of teixobactin require modifications, yet insufficient knowledge on its binding mode impedes the hunt for superior analogues. Thus far, teixobactins are assumed to kill bacteria by binding to cognate cell wall precursors (Lipid II and III). Here we present the binding mode of teixobactins in cellular membranes using solid-state NMR, microscopy, and affinity assays. We solve the structure of the complex formed by an improved teixobactin-analogue and Lipid II and reveal how teixobactins recognize a broad spectrum of targets. Unexpectedly, we find that teixobactins only weakly bind to Lipid II in cellular membranes, implying the direct interaction with cell wall precursors is not the sole killing mechanism. Our data suggest an additional mechanism affords the excellent activity of teixobactins, which can block the cell wall biosynthesis by capturing precursors in massive clusters on membranes.
Highlights
The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance
The chemical shifts report on the secondary structure[15] and show that the N-terminus of Lipid II-bound [R4L10]-teixobactin adopts a β-strand conformation (Fig. 1d), which matches with its high rigidity (Supplementary Fig. 2). β-structuring was observed in a teixobactin–sulfate complex in water[11] and in micelles with a truncated Lipid II variant[12]
The structure provides a wealth of information on the pharmacophore and demonstrates that teixobactins balance specific and fuzzy binding to recognize a maximal number of targets and to minimize the likelihood of resistance development
Summary
The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance. We present the binding mode of teixobactins in cellular membranes using solidstate NMR, microscopy, and affinity assays. We find that teixobactins only weakly bind to Lipid II in cellular membranes, implying the direct interaction with cell wall precursors is not the sole killing mechanism. Teixobactin is a natural undecapeptide from Eleftheria terrae that comprises several uncommon residues including D-amino-acids and L-allo-enduracididine, with the last four residues forming a ring motif. Given that it inhibits bacterial cell wall synthesis by targeting conserved non-proteinogenic molecules (Lipid II and III) in the plasma-membrane (Fig. 1a)[1], development of resistance against teixobactin is difficult[2,3,4]. All NMR spectra were acquired at 950 MHz. g Lipid II segregation caused by teixobactins visualized by fluorescence microscopy: GUVs doped with
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