Project Details
Projekt
Unlocking the functional potential of specialized metabolites in Eubacteriales from the human gut
Subject Area
Metabolism, Biochemistry and Genetics of Microorganisms
Microbial Ecology and Applied Microbiology
Microbial Ecology and Applied Microbiology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564360227
Natural products (NPs) from gut microbes are chemically diverse but functionally underexplored. Our previous work on gut bacterial isolates revealed chemically and biologically uncharacterized biosynthetic pathways encoding for RiPPs (ribosomally synthesized and post-translationally modified peptides) specific to members of the phylum Bacillota. In this project, we will elucidate the structure/function relationship within this new class of NPs within Eubacteriales, namely Clostridium and Blautia spp. We will thereby establish Blautia wexlerae as a new model organism and elucidate the functional diversity of its entire specialized metabolome, relying on our complementary expertise in biomolecular NP chemistry, genetic engineering, anaerobic cultivation, and microbial ecology. A toolbox will be developed to biotechnologically produce, purify, and chemically characterize the target NPs and create knockout strains and pooled transposon (Tn) mutant libraries of producing and target strains (i.e., sensitive to the NPs). Antimicrobial and collateral effects on the host will be determined using in-vitro and in-vivo assays. Effects on the target strains and the underlying mechanisms will be studied using both, time-series proteomics analysis in the presence/absence of NPs and Tn mutant libraries screening. Putative molecular targets will be validated in-vitro using native NPs and/or (semi)synthetic probes. A synthetic community (syncom) of human gut bacteria (www.hibc.rwth-aachen.de) will be designed and supplemented with producing, engineered, and target strains to study the functional role of the new peptides under native conditions in gnotobiotic mice. This work will unlock previously unknown microbial functions in the gut and open new avenues for targeted manipulation of the ecosystem, which fits perfectly with the scope of SPP2474.
DFG Programme
Priority Programmes
