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Published on: October 9, 2017
Total Synthesis and Biological Evaluation of Paenilamicins from the Honey Bee Pathogen Paenibacillus larvae
Timur Bulatov1, Sebastian Gensel1, Andi Mainz1
1Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623 Berlin, Germany.
Abstract:
Paenilamicins are a group of complex polycationic peptide secondary metabolites with antibacterial and antifungal activities produced by the devastating honey bee brood pathogen Paenibacillus larvae causing the lethal brood disease American Foulbrood (AFB). Here, we report the convergent total synthesis and structural revision of paenilamicin B2. Specific stereoisomers of paenilamicin B2 were synthesized for unambiguous confirmation of the natural product structure and for evaluation of biological activities. These studies revealed the N-terminal fragment of paenilamicin as an important pharmacophore. Infection assays using bee larvae and the insect pathogen Bacillus thuringiensis demonstrated that paenilamicins outcompete bacterial competitors in the ecological niche of P. larvae. Finally, we show first data that classifies paenilamicins as potential ribosome inhibitors. Hence, our synthesis route is a further step for understanding the pathogenicity of P. larvae and for thorough structure-activity-relationship as well as mode-of-action studies in the near future.
Insights
Researchers synthesized paenilamicin B2, revealing its N-terminal fragment as a key pharmacophore. These complex peptides combat American Foulbrood (AFB) by inhibiting bacterial competitors and potentially acting as ribosome inhibitors.
Area of Science:
- Natural Product Synthesis
- Chemical Biology
- Microbiology
Background:
- Paenilamicins are polycationic peptides produced by *Paenibacillus larvae*, the pathogen causing American Foulbrood (AFB) in honey bees.
- These secondary metabolites exhibit antibacterial and antifungal properties, playing a role in the pathogen's ecological niche.
Purpose of the Study:
- To achieve the total synthesis and structural revision of paenilamicin B2.
- To evaluate the biological activities of synthesized paenilamicin B2 stereoisomers.
- To investigate the mode of action and pathogenicity of paenilamicins.
Main Methods:
- Convergent total synthesis of paenilamicin B2 stereoisomers.
- Structural confirmation and revision of the natural product.
- Infection assays using bee larvae and *Bacillus thuringiensis*.
- Preliminary ribosome inhibition assays.
Main Results:
- Successful synthesis and structural revision of paenilamicin B2.
- Identification of the N-terminal fragment as a crucial pharmacophore.
- Demonstration that paenilamicins outcompete bacterial competitors in the *P. larvae* niche.
- Initial evidence suggests paenilamicins function as ribosome inhibitors.
Conclusions:
- The total synthesis provides a platform for detailed structure-activity relationship studies.
- Paenilamicins are potent inhibitors of bacterial competitors and potential ribosome inhibitors.
- Understanding paenilamicin synthesis and function aids in studying *P. larvae* pathogenicity.
