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

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. 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 and Markus Weingarth ()
Additional contact information
Rhythm Shukla: Utrecht University
Francesca Lavore: Utrecht University
Sourav Maity: Zernike Instituut, Rijksuniversiteit Groningen
Maik G. N. Derks: Utrecht University
Chelsea R. Jones: University of California Irvine
Bram J. A. Vermeulen: Utrecht University
Adéla Melcrová: Zernike Instituut, Rijksuniversiteit Groningen
Michael A. Morris: University of California Irvine
Lea Marie Becker: Utrecht University
Xiaoqi Wang: Utrecht University
Raj Kumar: Utrecht University
João Medeiros-Silva: Utrecht University
Roy A. M. Beekveld: Utrecht University
Alexandre M. J. J. Bonvin: Utrecht University
Joseph H. Lorent: Utrecht University
Moreno Lelli: University of Florence
James S. Nowick: University of California Irvine
Harold D. MacGillavry: Utrecht University
Aaron J. Peoples: NovoBiotic Pharmaceuticals
Amy L. Spoering: NovoBiotic Pharmaceuticals
Losee L. Ling: NovoBiotic Pharmaceuticals
Dallas E. Hughes: NovoBiotic Pharmaceuticals
Wouter H. Roos: Zernike Instituut, Rijksuniversiteit Groningen
Eefjan Breukink: Utrecht University
Kim Lewis: Northeastern University
Markus Weingarth: Utrecht University

Nature, 2022, vol. 608, issue 7922, 390-396

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05019-y

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