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

authored by: 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.
Organisation(s): Institute of Food Chemistry
External Organisation(s): Saarland University
Helmholtz Centre for Infection Research (HZI)
Universität Zürich (UZH)
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
German Center for Infection Research (DZIF)
Type: Article
Journal: Journal of the American Chemical Society
Volume: 146
Pages: 8981-8990
No. of pages: 10
ISSN: 0002-7863
Publication date: 03.04.2024
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: Catalysis, Chemistry(all), Biochemistry, Colloid and Surface Chemistry
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Electronic version(s): https://doi.org/10.1021/jacs.3c13208 (Access: Open)