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)