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. 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

doi:10.1038/s41586-022-05019-y

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. van Beekveld, Alexandre M.J.J. Bonvin, Joseph H. Lorent, Moreno Lelli, James S. Nowick, Harold D. MacGillavry, Aaron J. Peoples, Amy L. SpoeringLosee L. Ling, Dallas E. Hughes, Wouter H. Roos, Eefjan Breukink, Kim Lewis, Markus Weingarth^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 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.

Original language	English
Pages (from-to)	390-396
Number of pages	7
Journal	Nature
Volume	608
Issue number	7922
DOIs	https://doi.org/10.1038/s41586-022-05019-y
Publication status	Published - 11 Aug 2022

Bibliographical 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).

Funding

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.

Keywords

Analogs
Component
Elucidation
Enduracididine
Nmr
Peptide antibiotics
Precursor lipid ii
Solid-state
Staphylococcus-aureus
Target

Access to Document

10.1038/s41586-022-05019-yLicence: CC BY

s41586-022-05019-yFinal published version, 29.3 MBLicence: CC BY

Cite this

Shukla, R., Lavore, F., Maity, S., Derks, M. G. N., Jones, C. R., Vermeulen, B. J. A., Melcrová, A., Morris, M. A., Becker, L. M., Wang, X., Kumar, R., Medeiros-Silva, J., van Beekveld, R. A. M., Bonvin, A. M. J. J., Lorent, J. H., Lelli, M., Nowick, J. S., MacGillavry, H. D., Peoples, A. J., ... Weingarth, M. (2022). Teixobactin kills bacteria by a two-pronged attack on the cell envelope. Nature, 608(7922), 390-396. https://doi.org/10.1038/s41586-022-05019-y

@article{9f967b436aef4bde9178a7cc6309e210,

title = "Teixobactin kills bacteria by a two-pronged attack on the cell envelope",

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 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.",

keywords = "Analogs, Component, Elucidation, Enduracididine, Nmr, Peptide antibiotics, Precursor lipid ii, Solid-state, Staphylococcus-aureus, Target",

author = "Rhythm Shukla and Francesca Lavore and Sourav Maity and Derks, {Maik G.N.} and Jones, {Chelsea R.} and Vermeulen, {Bram J.A.} and Ad{\'e}la Melcrov{\'a} and Morris, {Michael A.} and Becker, {Lea Marie} and Xiaoqi Wang and Raj Kumar and Jo{\~a}o Medeiros-Silva and {van Beekveld}, {Roy A.M.} and Bonvin, {Alexandre M.J.J.} and Lorent, {Joseph H.} and Moreno Lelli and Nowick, {James S.} and MacGillavry, {Harold D.} and Peoples, {Aaron J.} and Spoering, {Amy L.} and Ling, {Losee L.} and Hughes, {Dallas E.} and Roos, {Wouter H.} and Eefjan Breukink and Kim Lewis and Markus Weingarth",

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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = aug,

day = "11",

doi = "10.1038/s41586-022-05019-y",

language = "English",

volume = "608",

pages = "390--396",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7922",

}

Shukla, R, Lavore, F, Maity, S, Derks, MGN, Jones, CR, Vermeulen, BJA, Melcrová, A, Morris, MA, Becker, LM, Wang, X, Kumar, R, Medeiros-Silva, J, van Beekveld, RAM , Bonvin, AMJJ, Lorent, JH, Lelli, M, Nowick, JS, MacGillavry, HD, Peoples, AJ, Spoering, AL, Ling, LL, Hughes, DE, Roos, WH, Breukink, E, Lewis, K & Weingarth, M 2022, 'Teixobactin kills bacteria by a two-pronged attack on the cell envelope', Nature, vol. 608, no. 7922, pp. 390-396. https://doi.org/10.1038/s41586-022-05019-y

TY - JOUR

T1 - Teixobactin kills bacteria by a two-pronged attack on the cell envelope

AU - Shukla, Rhythm

AU - Lavore, Francesca

AU - Maity, Sourav

AU - Derks, Maik G.N.

AU - Jones, Chelsea R.

AU - Vermeulen, Bram J.A.

AU - Melcrová, Adéla

AU - Morris, Michael A.

AU - Becker, Lea Marie

AU - Wang, Xiaoqi

AU - Kumar, Raj

AU - Medeiros-Silva, João

AU - van Beekveld, Roy A.M.

AU - Bonvin, Alexandre M.J.J.

AU - Lorent, Joseph H.

AU - Lelli, Moreno

AU - Nowick, James S.

AU - MacGillavry, Harold D.

AU - Peoples, Aaron J.

AU - Spoering, Amy L.

AU - Ling, Losee L.

AU - Hughes, Dallas E.

AU - Roos, Wouter H.

AU - Breukink, Eefjan

AU - Lewis, Kim

AU - Weingarth, Markus

N1 - 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).

PY - 2022/8/11

Y1 - 2022/8/11

N2 - 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 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.

AB - 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 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.

KW - Analogs

KW - Component

KW - Elucidation

KW - Enduracididine

KW - Nmr

KW - Peptide antibiotics

KW - Precursor lipid ii

KW - Solid-state

KW - Staphylococcus-aureus

KW - Target

UR - http://www.scopus.com/inward/record.url?scp=85135286631&partnerID=8YFLogxK

U2 - 10.1038/s41586-022-05019-y

DO - 10.1038/s41586-022-05019-y

M3 - Article

C2 - 35922513

AN - SCOPUS:85135286631

SN - 0028-0836

VL - 608

SP - 390

EP - 396

JO - Nature

JF - Nature

IS - 7922

ER -

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

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this