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Biosynthesis of bicyclic peptides with antibiotic properties

Subject Area Biological and Biomimetic Chemistry
Biochemistry
Term since 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 545372354
 
Bicyclic peptides are promising antibiotic lead structures for the treatment of infections caused by Gram-negative bacteria. Two bicyclic peptides have recently been discovered: darobactins and dynobactins. They belong to a family of ribosomally-produced and post-translationally-modified peptides (RiPPs) that are biosynthesized by a radical S-adenosyl methionine (RaS) enzyme. The later recognizes the precursor peptide and catalyses two intrapeptide crosslinks, producing a mature peptide with unique antibiotic properties that specifically inhibits BamA, a key component of the beta-barrel assembly machinery, essential for the proper folding of outer membrane proteins in Gram-negative bacteria. The possibility of obtaining novel compounds based on bicyclic peptides is limited because of the lack of structural information and because in vitro and in vivo production in heterologous expression systems faces multiple obstacles. To circumvent these hurdles, we will implement a novel approach based on the integration of our preliminary work on computational tools, analytical and functional studies, and structural biology. This approach enables to integrate enzyme-precursor peptide pairs into feedback loops designed to produce and characterise them in vivo and in vitro, and to obtain structural information by X-ray crystallography and CryoEM. As final products we aim to, 1) develop open source methods available to the RiPP community that will allow to identify coevolving motifs in other enzymes, 2) generate structural information for this subclass of RiPP modifying proteins and obtain a detailed mechanism of the enzymatic reactions that could be extrapolated to other RaS families and 3) implement high-throughput methods for in vivo production and characterisation of novel bioactive bicyclic peptides.
DFG Programme Research Grants
International Connection France
 
 

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