
==== Front
bioRxiv
BIORXIV
bioRxiv
Cold Spring Harbor Laboratory

10.1101/2024.05.21.595107
preprint
1
Article
Paenilamicins from the honey bee pathogen Paenibacillus larvae are context-specific translocation inhibitors of protein synthesis
Koller Timm O.
Berger Max J.
Morici Martino
Paternoga Helge
Bulatov Timur
Di Stasi Adriana
Dang Tam http://orcid.org/0000-0002-3602-1917

Mainz Andi
Raulf Karoline
Crowe-McAuliffe Caillan
Scocchi Marco
Mardirossian Mario
Beckert Bertrand
Vázquez-Laslop Nora
Mankin Alexander
Süssmuth Roderich D. http://orcid.org/0000-0001-7027-2069

Wilson Daniel N. http://orcid.org/0000-0003-3816-3828

21 5 2024
2024.05.21.595107http://biorxiv.org/lookup/doi/10.1101/2024.05.21.595107
nihpp-2024.05.21.595107.pdf
Abstract

The paenilamicins are a group of hybrid non-ribosomal peptide-polyketide compounds produced by the honey bee pathogen Paenibacillus larvae that display activity against Gram-positive pathogens, such as Staphylococcus aureus . While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here, we have determined structures of the paenilamicin PamB2 stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site tRNAs. In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms utilized by P. larvae . We could further demonstrate that PamB2 interferes with the translocation of mRNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a new class of context-specific translocation inhibitors.
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pmc
