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

verfasst von: 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
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.
Organisationseinheit(en): Institut für Lebensmittelchemie
Externe Organisation(en): Universität des Saarlandes
Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Universität Zürich (UZH)
Helmholtz-Institut für Pharmazeutische Forschung Saarland (HIPS)
Deutsches Zentrum für Infektionsforschung (DZIF)
Typ: Artikel
Journal: Journal of the American Chemical Society
Band: 146
Seiten: 8981-8990
Anzahl der Seiten: 10
ISSN: 0002-7863
Publikationsdatum: 03.04.2024
Publikationsstatus: Veröffentlicht
Peer-reviewed: Ja
ASJC Scopus Sachgebiete: Katalyse, Chemie (insg.), Biochemie, Kolloid- und Oberflächenchemie
Ziele für nachhaltige Entwicklung: SDG 3 – Gute Gesundheit und Wohlergehen
Elektronische Version(en): https://doi.org/10.1021/jacs.3c13208 (Zugang: Offen)

BibTeX

@article{1bb67b9a1f534b1c823da89655cf5216,
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.",
author = "Sebastian Adam and Franziska Fries and {von Tesmar}, Alexander and Sari Rasheed and Selina Deckarm and Sousa, {Carla F.} and Roman Reber{\v s}ek and Timo Risch and Stefano Mancini and Jennifer Herrmann and Jesko Koehnke and Kalinina, {Olga V.} and Rolf M{\"u}ller",
note = "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.). ",
year = "2024",
month = apr,
day = "3",
doi = "10.1021/jacs.3c13208",
language = "English",
volume = "146",
pages = "8981--8990",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "13",
}