The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autoren

  • Sebastian Adam
  • Franziska Fries
  • Alexander von Tesmar
  • Sari Rasheed
  • Selina Deckarm
  • Carla F. Sousa
  • Roman Reberšek
  • Timo Risch
  • Stefano Mancini
  • Jennifer Herrmann
  • Jesko Koehnke
  • Olga V. Kalinina
  • Rolf Müller

Organisationseinheiten

Externe Organisationen

  • Universität des Saarlandes
  • Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
  • Universität Zürich (UZH)
  • Helmholtz-Institut für Pharmazeutische Forschung Saarland (HIPS)
  • Deutsches Zentrum für Infektionsforschung (DZIF)
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Details

OriginalspracheEnglisch
Seiten (von - bis)8981-8990
Seitenumfang10
FachzeitschriftJournal of the American Chemical Society
Jahrgang146
Ausgabenummer13
Frühes Online-Datum21 März 2024
PublikationsstatusVeröffentlicht - 3 Apr. 2024

Abstract

The rapid development of antibiotic resistance, especially among difficult-to-treat Gram-negative bacteria, is recognized as a serious and urgent threat to public health. The detection and characterization of novel resistance mechanisms are essential to better predict the spread and evolution of antibiotic resistance. Corramycin is a novel and modified peptidic antibiotic with activity against several Gram-negative pathogens. We demonstrate that the kinase ComG, part of the corramycin biosynthetic gene cluster, phosphorylates and thereby inactivates corramycin, leading to the resistance of the host. Remarkably, we found that the closest structural homologues of ComG are aminoglycoside phosphotransferases; however, ComG shows no activity toward this class of antibiotics. The crystal structure of ComG in complex with corramycin reveals that corramycin adopts a β-hairpin-like structure and allowed us to define the changes leading to a switch in substrate from sugar to peptide. Bioinformatic analyses suggest a limited occurrence of ComG-like proteins, which along with the absence of cross-resistance to clinically used drugs positions corramycin as an attractive antibiotic for further development.

ASJC Scopus Sachgebiete

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Zitieren

The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG. / Adam, Sebastian; Fries, Franziska; von Tesmar, Alexander et al.
in: Journal of the American Chemical Society, Jahrgang 146, Nr. 13, 03.04.2024, S. 8981-8990.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Adam, S, Fries, F, von Tesmar, A, Rasheed, S, Deckarm, S, Sousa, CF, Reberšek, R, Risch, T, Mancini, S, Herrmann, J, Koehnke, J, Kalinina, OV & Müller, R 2024, 'The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG', Journal of the American Chemical Society, Jg. 146, Nr. 13, S. 8981-8990. https://doi.org/10.1021/jacs.3c13208
Adam, S., Fries, F., von Tesmar, A., Rasheed, S., Deckarm, S., Sousa, C. F., Reberšek, R., Risch, T., Mancini, S., Herrmann, J., Koehnke, J., Kalinina, O. V., & Müller, R. (2024). The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG. Journal of the American Chemical Society, 146(13), 8981-8990. https://doi.org/10.1021/jacs.3c13208
Adam S, Fries F, von Tesmar A, Rasheed S, Deckarm S, Sousa CF et al. The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG. Journal of the American Chemical Society. 2024 Apr 3;146(13):8981-8990. Epub 2024 Mär 21. doi: 10.1021/jacs.3c13208
Adam, Sebastian ; Fries, Franziska ; von Tesmar, Alexander et al. / The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG. in: Journal of the American Chemical Society. 2024 ; Jahrgang 146, Nr. 13. S. 8981-8990.
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title = "The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG",
abstract = "The rapid development of antibiotic resistance, especially among difficult-to-treat Gram-negative bacteria, is recognized as a serious and urgent threat to public health. The detection and characterization of novel resistance mechanisms are essential to better predict the spread and evolution of antibiotic resistance. Corramycin is a novel and modified peptidic antibiotic with activity against several Gram-negative pathogens. We demonstrate that the kinase ComG, part of the corramycin biosynthetic gene cluster, phosphorylates and thereby inactivates corramycin, leading to the resistance of the host. Remarkably, we found that the closest structural homologues of ComG are aminoglycoside phosphotransferases; however, ComG shows no activity toward this class of antibiotics. The crystal structure of ComG in complex with corramycin reveals that corramycin adopts a β-hairpin-like structure and allowed us to define the changes leading to a switch in substrate from sugar to peptide. Bioinformatic analyses suggest a limited occurrence of ComG-like proteins, which along with the absence of cross-resistance to clinically used drugs positions corramycin as an attractive antibiotic for further development.",
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AU - Adam, Sebastian

AU - Fries, Franziska

AU - von Tesmar, Alexander

AU - Rasheed, Sari

AU - Deckarm, Selina

AU - Sousa, Carla F.

AU - Reberšek, Roman

AU - Risch, Timo

AU - Mancini, Stefano

AU - Herrmann, Jennifer

AU - Koehnke, Jesko

AU - Kalinina, Olga V.

AU - Müller, Rolf

N1 - Funding Information: This study was supported by the German Centre for Infection Research (DZIF) in the project “Development of corramycin as an antibiotic against Gram-negative bacteria” (project: TTU 09.827, funding code: 8004809827) and the European Research Council (ERC CoG 101002326) (to J.K.).

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