Molecular basis of antibiotic self-resistance in a bee larvae pathogen

Tam Dang, Bernhard Loll, Sebastian Müller, Ranko Skobalj, Julia Ebeling, Timur Bulatov, Sebastian Gensel, Josefine Göbel, Markus C. Wahl, Elke Genersch, Andi Mainz and Roderich D. Süssmuth ()
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Tam Dang: Technische Universität Berlin
Bernhard Loll: Freie Universität Berlin
Sebastian Müller: Technische Universität Berlin
Ranko Skobalj: Technische Universität Berlin
Julia Ebeling: Institute for Bee Research, Department of Molecular Microbiology and Bee Diseases
Timur Bulatov: Technische Universität Berlin
Sebastian Gensel: Technische Universität Berlin
Josefine Göbel: Institute for Bee Research, Department of Molecular Microbiology and Bee Diseases
Markus C. Wahl: Freie Universität Berlin
Elke Genersch: Institute for Bee Research, Department of Molecular Microbiology and Bee Diseases
Andi Mainz: Technische Universität Berlin
Roderich D. Süssmuth: Technische Universität Berlin

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29829-w

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