Abstract
The emerging antibiotics-resistance problem has underlined the urgent need for novel antimicrobial agents. Lantibiotics (lanthionine-containing antibiotics) are promising candidates to alleviate this problem. Nisin, a member of this family, has a unique pore-forming activity against bacteria. It binds to lipid II, the essential precursor of cell wall synthesis. As a result, the membrane permeabilization activity of nisin is increased by three orders of magnitude. Here we report the solution structure of the complex of nisin and lipid II. The structure shows a novel lipid II–binding motif in which the pyrophosphate moiety of lipid II is primarily coordinated by the N-terminal backbone amides of nisin via intermolecular hydrogen bonds. This cage structure provides a rationale for the conservation of the lanthionine rings among several lipid II–binding lantibiotics. The structure of the pyrophosphate cage offers a template for structure-based design of novel antibiotics.
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Acknowledgements
This work was in part supported through the National NMR facility at Utrecht University from the Netherlands Organization for Chemical Research (NWO-CW). A.M.J.J.B. is a recipient of a NWO Jonge Chemici grant. A.M.G.L. is supported by NWO-STW grant 349-5257. We thank E.J. Smid (NIZO-food research) for his help with the preparation of 15N-labeled nisin.
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Supplementary Fig. 1
Chemical shift perturbations upon nisin–3LII complexation. (PDF 250 kb)
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Hsu, ST., Breukink, E., Tischenko, E. et al. The nisin–lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics. Nat Struct Mol Biol 11, 963–967 (2004). https://doi.org/10.1038/nsmb830
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DOI: https://doi.org/10.1038/nsmb830
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