Project Details
Projekt
UNCODE - Uncovering New Clostridial Gene Functions Using Off-Target Drug Effects on Human Gut Microbes
Subject Area
Metabolism, Biochemistry and Genetics of Microorganisms
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564241213
Many medicinal drugs inadvertently disrupt the human gut microbiome, often by directly inhibiting the growth of specific bacterial species. However, the molecular mechanisms behind these effects remain poorly understood, largely because traditional bacterial model organisms do not show the same sensitivity to medicinal drugs as gut microbiome members. This project leverages drug off-target effects to uncover novel cellular processes in non-model gut microbes by combining expertise in drug-microbiome interactions and chemical biology. We will focus on nervous-system-targeting drugs, such as selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, which broadly impact the fitness of gut bacteria of the phylum Bacillota. We have selected Clostridium sporogenes as a novel model species. It is a Gram-positive, spore-forming, anaerobic bacterium with a poorly annotated genome and is strongly affected by SSRIs. Preliminary work using Affinity-based Protein Profiling (AfBPP) has identified two potential fluoxetine interaction partners in C. sporogenes: a P-type Ca²⁺ ATPase and a copper-containing amine oxidase, which we hypothesize are critically linked to the growth of this bacterium. We will validate fluoxetine targets through loss-of-function studies in knockout strains and recombinant expression assays, using a variety of functional and enzymatic assays. Additionally, we will conduct forward genetics screens using pooled transposon libraries and proteomic analyses to identify genome-wide pathways affected by fluoxetine exposure. This approach will reveal key factors that influence C. sporogenes’ response to SSRIs, shedding light on the mechanisms that affect its fitness and lifestyle. Finally, we will explore whether the identified mechanisms extend to other SSRIs and gut bacterial species. This task will both benefit from and contribute to the datasets, resources, and genome-wide genetic tools being developed within the SPP 2474 consortium. Specifically, it will foster synergies with other SPP projects focused on small bioactive molecules and their interactions with gut bacteria, as well as with research on members of the Bacillota phylum. Ultimately, this research will provide valuable insights into the specific and general responses of gut microbes to human medicinal drugs, while uncovering novel bacterial gene functions and physiological processes.
DFG Programme
Priority Programmes
International Connection
United Kingdom
Cooperation Partner
Professor Rob Finn
