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Conjugative-killer plasmids, a novel antimicrobial alternative

Project description

Precision medicine against bacterial infections

In the battle against bacterial infections, the critical challenge lies in eliminating harmful pathogens without disrupting the delicate balance of our microbiota or fuelling antimicrobial resistance. With the support of the Marie Skłodowska-Curie Actions programme, the CoKiP project will harness genetic modules inspired by toxin-intein systems to selectively target and eliminate pathogens like Salmonella spp., Shigella spp., and Klebsiella pneumoniae while preserving the beneficial members of our microbiome. This approach promises to cure diseases while addressing the growing concerns of microbiota imbalances and antimicrobial resistance. Once validated in laboratory settings, the system will undergo testing in a Caernorhabditis elegans model, either for the elimination of specific disease-causing pathogens or as a probiotic agent to counteract pathogenic colonisation.

Objective

Targeted killing of pathogenic bacteria without harming beneficial members of the host microbiota holds promise as a strategy to cure disease and limit both imbalances in the microbiota and development of antimicrobial resistance. Recent work from the Unit de Plasticit du Gnome Bactrien has demonstrated that genetic modules based on toxin-intein systems delivered by conjugation are highly effective antimicrobials agents, able to selectively kill Vibrio cholerae in mixed populations. In this line of work, the project described in this proposal aims at adapting the aforementioned system to other pathogens of clinical importance (Salmonella spp. Shigella spp and Klebsiella pneumoniae) by including new toxin modules whose expression depends on transcriptional factors that are exclusively present in the targeted bacteria. Additionally, to ensure an efficient dissemination and maintenance across the microbial gut population, we intent to engineer conjugative plasmids to be transferred and maintained between Enterobacteriaceae and Bacteroides, one of the main constituents of the gut microbiome. Once validated under laboratory conditions, the system will be assayed in a Caernorhabditis elegans model, either with the aim of eliminating a specific pathogen causing disease or as a probiotic agent against pathogenic colonization. The results obtained from these preliminary tests will direct the refinements needed for the generation of an effective tool against antimicrobial resistant pathogens in a real scenario.

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Coordinator

INSTITUT PASTEUR
Net EU contribution
€ 195 914,88
Address
RUE DU DOCTEUR ROUX 25-28
75724 Paris
France

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Region
Ile-de-France Ile-de-France Hauts-de-Seine
Activity type
Research Organisations
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Total cost
No data