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Main Title: Molecular basis of antibiotic self-resistance in a bee larvae pathogen
Author(s): Dang, Tam
Loll, Bernhard
Müller, Sebastian
Skobalj, Ranko
Ebeling, Julia
Bulatov, Timur
Gensel, Sebastian
Göbel, Josefine
Wahl, Markus C.
Genersch, Elke
Mainz, Andi
Süssmuth, Roderich D.
Type: Article
Abstract: Paenibacillus larvae, the causative agent of the devastating honey-bee disease American Foulbrood, produces the cationic polyketide-peptide hybrid paenilamicin that displays antibacterial and antifungal activity. Its biosynthetic gene cluster contains a gene coding for the N-acetyltransferase PamZ. We show that PamZ acts as self-resistance factor in Paenibacillus larvae by deactivation of paenilamicin. Using tandem mass spectrometry, nuclear magnetic resonance spectroscopy and synthetic diastereomers, we identified the N-terminal amino group of the agmatinamic acid as the N-acetylation site. These findings highlight the pharmacophore region of paenilamicin, which we very recently identified as a ribosome inhibitor. Here, we further determined the crystal structure of PamZ:acetyl-CoA complex at 1.34 Å resolution. An unusual tandem-domain architecture provides a well-defined substrate-binding groove decorated with negatively-charged residues to specifically attract the cationic paenilamicin. Our results will help to understand the mode of action of paenilamicin and its role in pathogenicity of Paenibacillus larvae to fight American Foulbrood.
Subject(s): antimicrobial resistance
natural products
structural biology
Issue Date: 29-Apr-2022
Date Available: 27-Jun-2022
Language Code: en
DDC Class: 540 Chemie und zugeordnete Wissenschaften
Sponsor/Funder: TU Berlin, Open-Access-Mittel – 2022
DFG, 279410221, Interdisziplinäre Studien zu nichtribosomalen Sekundärmetaboliten aus Paenibacillus larvae
DFG, 392923329, GRK 2473: Bioaktive Peptide - Innovative Aspekte zur Synthese und Biosynthese
Journal Title: Nature Communications
Publisher: Springer Nature
Volume: 13
Article Number: 2349
Publisher DOI: 10.1038/s41467-022-29829-w
EISSN: 2041-1723
TU Affiliation(s): Fak. 2 Mathematik und Naturwissenschaften » Inst. Chemie » FG Organische Chemie
Appears in Collections:Technische Universität Berlin » Publications

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