Pseudotetraivprolides from <i>Pseudomonas entomophila</i> Provide Insights into the Biosynthesis of Detoxin/Rimosamide‐Like Anti‐Antibiotics
Abstract
Abstract Novel variants of known natural product (NP) classes can provide valuable insights into their biosynthesis, mechanisms of action, and potential as drug leads across the entire class. Here, we describe a novel member of the widespread detoxine/rimosamide‐like (DRL) natural products, named pseudotetraivprolide, produced by Pseudomonas strains. Pseudotetraivprolide exhibits the characteristic DRL‐activity of protecting Bacillus cereus against the antibiotic blasticidin S. Through the generation of multiple deletion and complementation mutants, heterologous expression experiments, identification and structure elucidation of several derivatives, chemical synthesis of main derivatives, enzymatic characterization of individual biochemical steps, and detailed homology modelling of enzyme complexes, we elucidated key aspects of its biosynthesis. Our findings demonstrate that the primary metabolism‐derived malonyl CoA:ACP transacylase (FabD) functions as a trans ‐AT in the biosynthesis pathway. Furthermore, we suggest an order for all late‐stage modifications and assign a function for the three conserved hypothetical proteins PipDFG acting as last‐step acetylation complex responsible for stabilization and activation of the final product.
Article Details
Authors (14)
Edna Bode
Department of Natural Products in Organismic Interactions Max Planck Institute for Terrestrial Microbiology Marburg 35043 Germany
Julia Büllesbach
Molecular Biotechnology Department of Biosciences Goethe University Frankfurt Frankfurt am Main 60438 Germany
Kevin Bauer
Institute for Organic Chemistry Saarland University Saarbrücken 66123 Germany
Yan‐Ni Shi
Molecular Biotechnology Department of Biosciences Goethe University Frankfurt Frankfurt am Main 60438 Germany
Simon Reiners
Buchmann Institute for Molecular Life Sciences Institute of Organic Chemistry and Chemical Biology Goethe University Frankfurt Frankfurt am Main 60438 Germany
Ziheng Cui
Buchmann Institute for Molecular Life Sciences Institute of Organic Chemistry and Chemical Biology Goethe University Frankfurt Frankfurt am Main 60438 Germany
Petra Happel
Department of Natural Products in Organismic Interactions Max Planck Institute for Terrestrial Microbiology Marburg 35043 Germany
Yi‐Ming Shi
Department of Natural Products in Organismic Interactions Max Planck Institute for Terrestrial Microbiology Marburg 35043 Germany
Kevin Hoffmann
Department of Natural Products in Organismic Interactions Max Planck Institute for Terrestrial Microbiology Marburg 35043 Germany
Peter Grün
Department of Natural Products in Organismic Interactions Max Planck Institute for Terrestrial Microbiology Marburg 35043 Germany
Bianca Pommerenke
Department of Biochemistry & Synthetic Metabolism Max Planck Institute for Terrestrial Microbiology Marburg 35043 Germany
Uli Kazmaier
Martin Grininger
Buchmann Institute for Molecular Life Sciences Institute of Organic Chemistry and Chemical Biology Goethe University Frankfurt Frankfurt am Main 60438 Germany
Helge B. Bode
Department of Natural Products in Organismic Interactions