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, Allgemeine Chemie, 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)