Host defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism

Shehrazade Jekhmane; Maik G N Derks; Sourav Maity; Cornelis J Slingerland; Kamaleddin H M E Tehrani; João Medeiros-Silva; Vicky Charitou; Danique Ammerlaan; Céline Fetz; Naomi A Consoli; Rachel V K Cochrane; Eilidh J Matheson; Mick van der Weijde; Barend O W Elenbaas; Francesca Lavore; Ruud Cox; Joseph H Lorent; Marc Baldus; Markus Künzler; Moreno Lelli; Stephen A Cochrane; Nathaniel I Martin; Wouter H Roos; Eefjan Breukink; Markus Weingarth

doi:10.1038/s41564-024-01696-9

Host defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism

Shehrazade Jekhmane
, Maik G N Derks
, Sourav Maity
, Cornelis J Slingerland
, Kamaleddin H M E Tehrani
, João Medeiros-Silva
, Vicky Charitou
, Danique Ammerlaan
, Céline Fetz
, Naomi A Consoli
, Rachel V K Cochrane
, Eilidh J Matheson
, Mick van der Weijde
, Barend O W Elenbaas
, Francesca Lavore
, Ruud Cox
, Joseph H Lorent
, Marc Baldus
, Markus Künzler
, Moreno Lelli

Stephen A Cochrane, Nathaniel I Martin, Wouter H Roos, Eefjan Breukink, Markus Weingarth^*

^*Corresponding author for this work

Moleculaire Biofysica
Institute of Biology Leiden (IBL), Leiden University, PO Box 9505, Leiden 2300 RA, The NetherlandsLeiden Institute for Brain and Cognition (LIBC), Leiden University, c/o LUMC, Postzone C2-S, PO Box 9600, Leiden 2300 RC, The Netherlands
Utrecht University
Institute of Microbiology
University of Florence
Queen's University Belfast

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

Abstract

Antimicrobial resistance is a leading cause of mortality, calling for the development of new antibiotics. The fungal antibiotic plectasin is a eukaryotic host defence peptide that blocks bacterial cell wall synthesis. Here, using a combination of solid-state nuclear magnetic resonance, atomic force microscopy and activity assays, we show that plectasin uses a calcium-sensitive supramolecular killing mechanism. Efficient and selective binding of the target lipid II, a cell wall precursor with an irreplaceable pyrophosphate, is achieved by the oligomerization of plectasin into dense supra-structures that only form on bacterial membranes that comprise lipid II. Oligomerization and target binding of plectasin are interdependent and are enhanced by the coordination of calcium ions to plectasin's prominent anionic patch, causing allosteric changes that markedly improve the activity of the antibiotic. Structural knowledge of how host defence peptides impair cell wall synthesis will likely enable the development of superior drug candidates.

Original language	English
Pages (from-to)	1778-1791
Number of pages	14
Journal	Nature Reviews Microbiology
Volume	9
Issue number	7
Early online date	23 May 2024
DOIs	https://doi.org/10.1038/s41564-024-01696-9
Publication status	Published - Jul 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

This work was funded by the Netherlands Organization for Scientific Research (NWO, grant numbers 723.014.003 and 711.018.001 to M.W.). This project has received funding from the European Union\u2019s Horizon Europe grant and innovation programme under grant agreement number 101045485 (to M.W.). Experiments at the 950 and 1,200\u2009MHz instruments were supported by uNMR-NL, the National Roadmap Large-Scale NMR Facility of the Netherlands (NWO grant 184.032.207) and the uNMR-NL grid (NWO grant 184.035.002). Support by Instruct-ERIC (to M.L. and M.W.) is acknowledged. Support by project INFRAIA-02-2020 PANACEA (H2020, contract number 101008500, to M.L. and M.W.) is acknowledged. M.L. acknowledges the Fondazione CR Firenze for funding. M.L. acknowledges the financial support provided by the MUR - Dipartimenti di Eccellenza 2023-2027 (DICUS 2.0) to the Department of Chemistry \u2018Ugo Schiff\u2019 of the University of Florence. The present work was part of the research programme of the Netherlands Centre for One Health. Natural teixobactin was a kind gift from NovoBiotic Pharmaceuticals.

Funders	Funder number
Fondazione Cassa di Risparmio di Firenze
INFRAIA-02-2020 PANACEA
Università degli Studi di Firenze
Ministero dell’Istruzione, dell’Università e della Ricerca
European Union’s Horizon Europe grant and innovation programme	101045485, 184.035.002, 184.032.207
Dipartimenti di Eccellenza	2023-2027
Dipartimenti di Eccellenza
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	711.018.001, 723.014.003
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Horizon 2020 Framework Programme	101008500
Horizon 2020 Framework Programme

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s41564-024-01696-9Final published version, 12.2 MBLicence: CC BY

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Jekhmane, S., Derks, M. G. N., Maity, S., Slingerland, C. J., Tehrani, K. H. M. E., Medeiros-Silva, J., Charitou, V., Ammerlaan, D., Fetz, C., Consoli, N. A., Cochrane, R. V. K., Matheson, E. J., van der Weijde, M., Elenbaas, B. O. W., Lavore, F., Cox, R., Lorent, J. H., Baldus, M., Künzler, M., ... Weingarth, M. (2024). Host defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism. Nature Reviews Microbiology, 9(7), 1778-1791. https://doi.org/10.1038/s41564-024-01696-9

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abstract = "Antimicrobial resistance is a leading cause of mortality, calling for the development of new antibiotics. The fungal antibiotic plectasin is a eukaryotic host defence peptide that blocks bacterial cell wall synthesis. Here, using a combination of solid-state nuclear magnetic resonance, atomic force microscopy and activity assays, we show that plectasin uses a calcium-sensitive supramolecular killing mechanism. Efficient and selective binding of the target lipid II, a cell wall precursor with an irreplaceable pyrophosphate, is achieved by the oligomerization of plectasin into dense supra-structures that only form on bacterial membranes that comprise lipid II. Oligomerization and target binding of plectasin are interdependent and are enhanced by the coordination of calcium ions to plectasin's prominent anionic patch, causing allosteric changes that markedly improve the activity of the antibiotic. Structural knowledge of how host defence peptides impair cell wall synthesis will likely enable the development of superior drug candidates.",

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note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = jul,

doi = "10.1038/s41564-024-01696-9",

language = "English",

volume = "9",

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Jekhmane, S, Derks, MGN, Maity, S, Slingerland, CJ, Tehrani, KHME, Medeiros-Silva, J, Charitou, V, Ammerlaan, D, Fetz, C, Consoli, NA, Cochrane, RVK, Matheson, EJ, van der Weijde, M, Elenbaas, BOW, Lavore, F, Cox, R, Lorent, JH, Baldus, M, Künzler, M, Lelli, M, Cochrane, SA, Martin, NI, Roos, WH, Breukink, E & Weingarth, M 2024, 'Host defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism', Nature Reviews Microbiology, vol. 9, no. 7, pp. 1778-1791. https://doi.org/10.1038/s41564-024-01696-9

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T1 - Host defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism

AU - Jekhmane, Shehrazade

AU - Derks, Maik G N

AU - Maity, Sourav

AU - Slingerland, Cornelis J

AU - Tehrani, Kamaleddin H M E

AU - Medeiros-Silva, João

AU - Charitou, Vicky

AU - Ammerlaan, Danique

AU - Fetz, Céline

AU - Consoli, Naomi A

AU - Cochrane, Rachel V K

AU - Matheson, Eilidh J

AU - van der Weijde, Mick

AU - Elenbaas, Barend O W

AU - Lavore, Francesca

AU - Cox, Ruud

AU - Lorent, Joseph H

AU - Baldus, Marc

AU - Künzler, Markus

AU - Lelli, Moreno

AU - Cochrane, Stephen A

AU - Martin, Nathaniel I

AU - Roos, Wouter H

AU - Breukink, Eefjan

AU - Weingarth, Markus

PY - 2024/7

Y1 - 2024/7

N2 - Antimicrobial resistance is a leading cause of mortality, calling for the development of new antibiotics. The fungal antibiotic plectasin is a eukaryotic host defence peptide that blocks bacterial cell wall synthesis. Here, using a combination of solid-state nuclear magnetic resonance, atomic force microscopy and activity assays, we show that plectasin uses a calcium-sensitive supramolecular killing mechanism. Efficient and selective binding of the target lipid II, a cell wall precursor with an irreplaceable pyrophosphate, is achieved by the oligomerization of plectasin into dense supra-structures that only form on bacterial membranes that comprise lipid II. Oligomerization and target binding of plectasin are interdependent and are enhanced by the coordination of calcium ions to plectasin's prominent anionic patch, causing allosteric changes that markedly improve the activity of the antibiotic. Structural knowledge of how host defence peptides impair cell wall synthesis will likely enable the development of superior drug candidates.

AB - Antimicrobial resistance is a leading cause of mortality, calling for the development of new antibiotics. The fungal antibiotic plectasin is a eukaryotic host defence peptide that blocks bacterial cell wall synthesis. Here, using a combination of solid-state nuclear magnetic resonance, atomic force microscopy and activity assays, we show that plectasin uses a calcium-sensitive supramolecular killing mechanism. Efficient and selective binding of the target lipid II, a cell wall precursor with an irreplaceable pyrophosphate, is achieved by the oligomerization of plectasin into dense supra-structures that only form on bacterial membranes that comprise lipid II. Oligomerization and target binding of plectasin are interdependent and are enhanced by the coordination of calcium ions to plectasin's prominent anionic patch, causing allosteric changes that markedly improve the activity of the antibiotic. Structural knowledge of how host defence peptides impair cell wall synthesis will likely enable the development of superior drug candidates.

UR - https://www.scopus.com/pages/publications/85193978725

U2 - 10.1038/s41564-024-01696-9

DO - 10.1038/s41564-024-01696-9

M3 - Article

C2 - 38783023

SN - 1740-1526

VL - 9

SP - 1778

EP - 1791

JO - Nature Reviews Microbiology

JF - Nature Reviews Microbiology

IS - 7

ER -

Host defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism

Abstract

Bibliographical note

Funding

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