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

Autor: Shukla, Rhythm, Lavore, Francesca, Maity, Sourav, Derks, Maik G.N., Jones, Chelsea R., Vermeulen, Bram J.A., Melcrová, Adéla, Morris, Michael A., Becker, Lea Marie, Wang, Xiaoqi, Kumar, Raj, Medeiros-Silva, João, van Beekveld, Roy A.M., Bonvin, Alexandre M.J.J., Lorent, Joseph H., Lelli, Moreno, Nowick, James S., MacGillavry, Harold D., Peoples, Aaron J., Spoering, Amy L., Ling, Losee L., Hughes, Dallas E., Roos, Wouter H., Breukink, Eefjan, Lewis, Kim, Weingarth, Markus, Sub NMR Spectroscopy, Sub Membrane Biochemistry & Biophysics, Sub Cell Biology, NMR Spectroscopy, Celbiologie, Membrane Biochemistry and Biophysics
Přispěvatelé: Sub NMR Spectroscopy, Sub Membrane Biochemistry & Biophysics, Sub Cell Biology, NMR Spectroscopy, Celbiologie, Membrane Biochemistry and Biophysics, Molecular Biophysics
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Component
Target
Protein Structure
Secondary
Pyrrolidines
Nuclear Magnetic Resonance
Drug Resistance
Bacterial/drug effects
Drug Resistance
Anti-Bacterial Agents/chemistry
Bacteria/cytology
Lipids/chemistry
Microbial Sensitivity Tests
Molecular Dynamics Simulation
Microscopy
Atomic Force
Elucidation
Protein Structure
Secondary
Precursor lipid ii
Depsipeptides/chemistry
Cell Wall
Solid-state
Depsipeptides
Drug Resistance
Bacterial
Humans
Sugars/chemistry
Staphylococcus-aureus
General
Nuclear Magnetic Resonance
Biomolecular
Cell Wall/drug effects
Peptide antibiotics
Microscopy
Microbial Viability
Multidisciplinary
Bacteria
Cell Membrane/drug effects
Diphosphates/chemistry
Cell Membrane
Microbial Viability/drug effects
Bacterial/drug effects
Atomic Force
Enduracididine
Lipids
Nmr
Anti-Bacterial Agents
Diphosphates
Pyrrolidines/chemistry
Sugars
Analogs
Biomolecular
Zdroj: Nature, 608(7922), 390. Nature Research
Nature
Nature, 608(7922), 390-396. Nature Publishing Group
ISSN: 0028-0836
DOI: 10.1038/s41586-022-05019-y
Popis: 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.
Databáze: OpenAIRE
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