Grant: Project Grant

Bacterial conjugation plays a major role in propagating antibiotic resistance genes. Previous work by our group drew attention to the conjugative plasmid TP114 because of its remarkable efficiency in transferring genes within the gut microbiota. Since the gut microbiota is the habitat of a vast diversity of microorganisms, IncI2 conjugative plasmids similar to TP114 may significantly contribute to the spread of antibiotic-resistance genes to various opportunistic pathogens, thereby increasing the risk of hard-to-treat infections. On the other hand, the high transfer rates of TP114 also open avenues to develop pioneering microbiome editing technologies. For example, we have recently demonstrated that a single dose of an engineered probiotic harboring a TP114 derivative equipped with a CRISPR system was able to eliminate 99.9% of targeted antibiotic-resistant bacteria in the gut microbiota. The same engineered probiotic also cured an infection by an intestinal pathogen in a mouse model of infection. However, our knowledge about the biology of TP114 remains scarce, and the reasons explaining why TP114 outperforms the transfer rates of other conjugative plasmids remain unclear. We propose to deepen our understanding of the mechanisms employed by TP114 to transfer at high rates in the gut microbiota and to use this information to 1) identify potential strategies to inhibit the transfer of conjugative plasmids related to TP114 in the intestinal microbiota, and 2) engineer safer and more effective microbiome editing technologies. These advancements could eventually contribute to the fight against antibiotic resistance, and open up new therapeutic avenues to treat various diseases associated with specific bacterial populations residing in the gut microbiota.