An antibiotic from an uncultured bacterium binds to an immutable target

Rhythm Shukla; Aaron J Peoples; Kevin C Ludwig; Sourav Maity; Maik G N Derks; Stefania De Benedetti; Annika M Krueger; Bram J A Vermeulen; Theresa Harbig; Francesca Lavore; Raj Kumar; Rodrigo V Honorato; Fabian Grein; Kay Nieselt; Yangping Liu; Alexandre M J J Bonvin; Marc Baldus; Ulrich Kubitscheck; Eefjan Breukink; Catherine Achorn; Anthony Nitti; Christopher J Schwalen; Amy L Spoering; Losee Lucy Ling; Dallas Hughes; Moreno Lelli; Wouter H Roos; Kim Lewis; Tanja Schneider; Markus Weingarth

doi:10.1016/j.cell.2023.07.038

An antibiotic from an uncultured bacterium binds to an immutable target

Rhythm Shukla, Aaron J Peoples, Kevin C Ludwig, Sourav Maity, Maik G N Derks, Stefania De Benedetti, Annika M Krueger, Bram J A Vermeulen, Theresa Harbig, Francesca Lavore, Raj Kumar, Rodrigo V Honorato, Fabian Grein, Kay Nieselt, Yangping Liu, Alexandre M J J Bonvin, Marc Baldus, Ulrich Kubitscheck, Eefjan Breukink, Catherine AchornAnthony Nitti, Christopher J Schwalen, Amy L Spoering, Losee Lucy Ling, Dallas Hughes, Moreno Lelli, Wouter H Roos, Kim Lewis, Tanja Schneider^*, Markus Weingarth^*

^*Corresponding author for this work

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

Abstract

Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55PP, lipid II, and lipid III WTA). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.

Original language	English
Pages (from-to)	4059-4073.e27
Journal	Cell
Volume	186
Issue number	19
DOIs	https://doi.org/10.1016/j.cell.2023.07.038
Publication status	Published - 14 Sept 2023

Keywords

Anti-Bacterial Agents/isolation & purification
Bacteria
Biological Assay
Diphosphates
Soil Microbiology

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PIIS009286742300853XFinal published version, 17.7 MBLicence: CC BY

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Shukla, R., Peoples, A. J., Ludwig, K. C., Maity, S., Derks, M. G. N., De Benedetti, S., Krueger, A. M., Vermeulen, B. J. A., Harbig, T., Lavore, F., Kumar, R., Honorato, R. V., Grein, F., Nieselt, K., Liu, Y., Bonvin, A. M. J. J., Baldus, M., Kubitscheck, U., Breukink, E., ... Weingarth, M. (2023). An antibiotic from an uncultured bacterium binds to an immutable target. Cell, 186(19), 4059-4073.e27. https://doi.org/10.1016/j.cell.2023.07.038

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title = "An antibiotic from an uncultured bacterium binds to an immutable target",

abstract = "Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55PP, lipid II, and lipid III WTA). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development. ",

keywords = "Anti-Bacterial Agents/isolation & purification, Bacteria, Biological Assay, Diphosphates, Soil Microbiology",

author = "Rhythm Shukla and Peoples, {Aaron J} and Ludwig, {Kevin C} and Sourav Maity and Derks, {Maik G N} and {De Benedetti}, Stefania and Krueger, {Annika M} and Vermeulen, {Bram J A} and Theresa Harbig and Francesca Lavore and Raj Kumar and Honorato, {Rodrigo V} and Fabian Grein and Kay Nieselt and Yangping Liu and Bonvin, {Alexandre M J J} and Marc Baldus and Ulrich Kubitscheck and Eefjan Breukink and Catherine Achorn and Anthony Nitti and Schwalen, {Christopher J} and Spoering, {Amy L} and Ling, {Losee Lucy} and Dallas Hughes and Moreno Lelli and Roos, {Wouter H} and Kim Lewis and Tanja Schneider and Markus Weingarth",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = sep,

day = "14",

doi = "10.1016/j.cell.2023.07.038",

language = "English",

volume = "186",

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Shukla, R, Peoples, AJ, Ludwig, KC, Maity, S, Derks, MGN, De Benedetti, S, Krueger, AM, Vermeulen, BJA, Harbig, T, Lavore, F , Kumar, R, Honorato, RV, Grein, F, Nieselt, K, Liu, Y, Bonvin, AMJJ , Baldus, M, Kubitscheck, U, Breukink, E, Achorn, C, Nitti, A, Schwalen, CJ, Spoering, AL, Ling, LL, Hughes, D, Lelli, M, Roos, WH, Lewis, K, Schneider, T & Weingarth, M 2023, 'An antibiotic from an uncultured bacterium binds to an immutable target', Cell, vol. 186, no. 19, pp. 4059-4073.e27. https://doi.org/10.1016/j.cell.2023.07.038

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AU - Shukla, Rhythm

AU - Peoples, Aaron J

AU - Ludwig, Kevin C

AU - Maity, Sourav

AU - Derks, Maik G N

AU - De Benedetti, Stefania

AU - Krueger, Annika M

AU - Vermeulen, Bram J A

AU - Harbig, Theresa

AU - Lavore, Francesca

AU - Kumar, Raj

AU - Honorato, Rodrigo V

AU - Grein, Fabian

AU - Nieselt, Kay

AU - Liu, Yangping

AU - Bonvin, Alexandre M J J

AU - Baldus, Marc

AU - Kubitscheck, Ulrich

AU - Breukink, Eefjan

AU - Achorn, Catherine

AU - Nitti, Anthony

AU - Schwalen, Christopher J

AU - Spoering, Amy L

AU - Ling, Losee Lucy

AU - Hughes, Dallas

AU - Lelli, Moreno

AU - Roos, Wouter H

AU - Lewis, Kim

AU - Schneider, Tanja

AU - Weingarth, Markus

PY - 2023/9/14

Y1 - 2023/9/14

N2 - Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55PP, lipid II, and lipid III WTA). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.

AB - Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55PP, lipid II, and lipid III WTA). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.

KW - Anti-Bacterial Agents/isolation & purification

KW - Bacteria

KW - Biological Assay

KW - Diphosphates

KW - Soil Microbiology

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U2 - 10.1016/j.cell.2023.07.038

DO - 10.1016/j.cell.2023.07.038

M3 - Article

C2 - 37611581

SN - 0092-8674

VL - 186

SP - 4059-4073.e27

JO - Cell

JF - Cell

IS - 19

ER -

An antibiotic from an uncultured bacterium binds to an immutable target

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Keywords

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