Teixobactin kills bacteria by a two-pronged attack on the cell envelope
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
(2022) Nature, volume 608, issue 7922, pp. 390 - 396
(Article)
Abstract
Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance(1-3). Teixobactin(4) represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan(5). Here we unravel the mechanism of teixobactin at the atomic level using a combination
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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 beta-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 teixobactin(4). 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.
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Keywords: Analogs, Component, Elucidation, Enduracididine, Nmr, Peptide antibiotics, Precursor lipid ii, Solid-state, Staphylococcus-aureus, Target, General
ISSN: 0028-0836
Publisher: Nature Research
Note: Funding Information: This work was funded by the Netherlands Organisation for Scientific Research (NWO; grant numbers 723.014.003 and 711.018.001 to M.W., 680.91.007 to A.M. and 718.015.001 to A.M.J.J.B.). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 101045485 to M.W.). Experiments at the 950-MHz instrument were supported by μNMR-NL, an NWO-funded Roadmap NMR facility (no. 184.032.207). Support by Instruct-ERIC (to M.L. and M.W.) is acknowledged. The present work was part of the research programme of the Netherlands Centre for One Health ( www.ncoh.nl ). This work has been supported by iNEXT-Discovery (grant number 871037) and BioExcel (grant numbers 675728 and 823830), funded by the Horizon 2020 programme of the European Commission. M.L. acknowledges the support of Progetto Dipartimenti di Eccellenza 2018-2022 of the Department of Chemistry 'Ugo Schiff' of the University of Florence. Publisher Copyright: © 2022, The Author(s).
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