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, 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 these drugs.
Preliminary work using Affinity-based Protein Profiling (AfBPP) has identified two potential interaction partners in C. sporogenes, which we hypothesize are critically linked to the growth of this bacterium. We will validate these 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 drug exposure. This approach will reveal key factors that influence C. sporogenes’ response to drugs, shedding light on the mechanisms that affect its fitness and lifestyle. Finally, we will explore whether the identified mechanisms extend to other drug classes and gut bacterial species.