A new 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; Francesca Lavore; Rodrigo V Honorato; Fabian Grein; Alexandre Bonvin; 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:10.1101/2023.05.15.540765

A new 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, Francesca Lavore, Rodrigo V Honorato, Fabian Grein, Alexandre Bonvin, Ulrich Kubitscheck, Eefjan Breukink, Catherine Achorn, Anthony Nitti, Christopher J Schwalen, Amy L Spoering, Losee Lucy Ling, Dallas HughesMoreno Lelli, Wouter H Roos, Kim Lewis, Tanja Schneider, Markus Weingarth^*

^*Corresponding author for this work

Research output: Working paper › Preprint › Academic

Abstract

Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55 PP, Lipid II, Lipid 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 irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.

Original language	English
Publisher	bioRxiv
Pages	1-30
Number of pages	30
DOIs	https://doi.org/10.1101/2023.05.15.540765
Publication status	Published - 15 May 2023

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2023.05.15.540765v1.fullSubmitted manuscript, 6.25 MBLicence: CC BY-NC-ND

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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., Lavore, F., Honorato, R. V., Grein, F., Bonvin, A., Kubitscheck, U., Breukink, E., Achorn, C., Nitti, A., Schwalen, C. J., Spoering, A. L., Ling, L. L., ... Weingarth, M. (2023). A new antibiotic from an uncultured bacterium binds to an immutable target. (pp. 1-30). bioRxiv. https://doi.org/10.1101/2023.05.15.540765

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abstract = "Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55 PP, Lipid II, Lipid 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 irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline. ",

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 Francesca Lavore and Honorato, {Rodrigo V} and Fabian Grein and Alexandre Bonvin 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",

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Shukla, R, Peoples, AJ, Ludwig, KC, Maity, S, Derks, MGN, de Benedetti, S, Krueger, AM, Vermeulen, BJA, Lavore, F, Honorato, RV, Grein, F, Bonvin, A, 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 'A new antibiotic from an uncultured bacterium binds to an immutable target' bioRxiv, pp. 1-30. https://doi.org/10.1101/2023.05.15.540765

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AU - Ludwig, Kevin C

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AU - de Benedetti, Stefania

AU - Krueger, Annika M

AU - Vermeulen, Bram J A

AU - Lavore, Francesca

AU - Honorato, Rodrigo V

AU - Grein, Fabian

AU - Bonvin, Alexandre

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

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N2 - Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55 PP, Lipid II, Lipid 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 irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.

AB - Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55 PP, Lipid II, Lipid 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 irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.

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BT - A new antibiotic from an uncultured bacterium binds to an immutable target

PB - bioRxiv

ER -

A new antibiotic from an uncultured bacterium binds to an immutable target

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