Novel interventions for eliminating one- health mobile antimicrobial resistance genes from human and animal microbiomes

Antibiotic resistant bacteria pose a fundamental threat to human health. There is growing recognition that the genes that make bacteria resistant to antibiotics (AMR genes) are transferred between bacteria from agricultural animals and bacteria associated with humans. This exchange of AMR genes is mediated by self-replicating DNA molecules called plasmids that have the ability to transfer between bacterial cells. In this project we will test the ability of specialised viruses that target the plasmid transfer machinery to limit the spread of AMR genes in isolated pathogen populations and complex bacterial communities. Ultimately, this project will lead to the development of new phage based approaches for eradicating AMR genes from humans and agricultural animals that act as important sources of AMR genes, particularly in LMIC settings.

The most important cases of one-health antimicrobial resistance are caused by the rapid spread of plasmids carrying AMR genes between bacterial strains and species. In this project, we will test the of plasmid-dependent lytic bacteriophages (PDB) to selectively decontaminate bacterial communities by killing AMR plasmid-containing bacteria and by preventing the transfer of AMR plasmids to commensal and pathogen strains. First we will test the impact of key variables on the efficacy of PDB therapy (antibiotic treatment, bacterial diversity, phage mono culture or cocktail) using an established PDB-host system. We will then (i) screen an established collection of phages from agricultural sources to discover new PDBs that have activity against a broader range of one-health AMR plasmids and (ii) test the impact of the aforementioned key variables on the efficacy of these phage in vitro.