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Teixobactin kills bacteria by a two-pronged attack on the cell envelope

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Titel: Teixobactin kills bacteria by a two-pronged attack on the cell envelope
Autoren: Rhythm Shukla, Francesca Lavore, Sourav Maity, Maik G. N. Derks, Chelsea R. Jones, Bram J. A. Vermeulen, Adéla Melcrová, Michael A. Morris, Lea Marie Becker, Xiaoqi Wang, Raj Kumar, João Medeiros-Silva, Roy A. M. van Beekveld, Alexandre M. J. J. Bonvin, Joseph H. Lorent, Moreno Lelli, James S. Nowick, Harold D. MacGillavry, Aaron J. Peoples, Amy L. Spoering, Losee L. Ling, Dallas E. Hughes, Wouter H. Roos, Eefjan Breukink, Kim Lewis, Markus Weingarth
Weitere Verfasser: Sub NMR Spectroscopy, Sub Membrane Biochemistry & Biophysics, Sub Cell Biology, NMR Spectroscopy, Cell Biology, Neurobiology and Biophysics, Membrane Biochemistry and Biophysics, Celbiologie
Quelle: Nature
Nature, vol 608, iss 7922
Verlagsinformationen: Springer Science and Business Media LLC, 2022.
Publikationsjahr: 2022
Schlagwörter: Target, 0301 basic medicine, Secondary, Pyrrolidines, Drug Resistance, Anti-Bacterial Agents/chemistry, Bacteria/cytology, Microscopy, Atomic Force, Elucidation, Protein Structure, Secondary, Precursor lipid ii, Depsipeptides/chemistry, Solid-state, Cell Wall, Depsipeptides, Diphosphates, Drug Resistance, Bacterial, Humans, Lipids, Microbial Sensitivity Tests, Molecular Dynamics Simulation, Nuclear Magnetic Resonance, Biomolecular, Sugars, Anti-Bacterial Agents, Bacteria, Cell Membrane, Microbial Viability, Microscopy, 0303 health sciences, Diphosphates/chemistry, Bacterial, Bacterial/drug effects, Atomic Force, 3. Good health, Component, Protein Structure, Nuclear Magnetic Resonance, Lipids/chemistry, Article, 03 medical and health sciences, Sugars/chemistry, Staphylococcus-aureus, General, Cell Wall/drug effects, Peptide antibiotics, Cell Membrane/drug effects, Microbial Viability/drug effects, Enduracididine, Nmr, Pyrrolidines/chemistry, Analogs, Biomolecular
Beschreibung: Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1–3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.
Publikationsart: Article
Other literature type
Dateibeschreibung: application/pdf
Sprache: English
ISSN: 1476-4687
0028-0836
DOI: 10.1038/s41586-022-05019-y
Zugangs-URL: https://pubmed.ncbi.nlm.nih.gov/35922513
https://hdl.handle.net/11370/78c4d6a7-972c-4f0d-a88b-66de901089cb
https://doi.org/10.1038/s41586-022-05019-y
https://research.rug.nl/en/publications/78c4d6a7-972c-4f0d-a88b-66de901089cb
https://research-portal.uu.nl/en/publications/9f967b43-6aef-4bde-9178-a7cc6309e210
https://doi.org/10.1038/s41586-022-05019-y
https://dspace.library.uu.nl/handle/1874/422893
https://dspace.library.uu.nl/handle/1874/422875
https://escholarship.org/content/qt61v5j591/qt61v5j591.pdf
https://escholarship.org/uc/item/61v5j591
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) .
Dokumentencode: edsair.doi.dedup.....71a758c21eadc4b4daf2806d5db5df77
Datenbank: OpenAIRE
Beschreibung
Abstract:Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1–3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.
ISSN:14764687
00280836
DOI:10.1038/s41586-022-05019-y