Novel interventions for eliminating one-health mobile antimicrobial resistance genes from human and animal microbiomes
The most important cases of one-health antimicrobial resistance (AMR) are caused by dissemination of antibiotic resistance genes on mobile genetic elements. In this project, we will develop novel interventions aimed at selectively eliminating mobile AMR from complex human and animal microbiomes. We will focus on two urgent AMR problems: 1. AMR poses a critical health risk to neonates. We will develop sequence specific antimicrobials (SSA) and conjugative delivery systems to eliminate AMR from the neonatal microbiome. SSAs will include CRISPR-Cas9 systems that will target AMR plasmids, “killer cassettes” that will kill bacteria carrying mobile integrons that are key platforms for AMR, and inducible toxin-intein antimicrobials that will kill cells carrying AMR plasmids. We will test the efficacy of these systems using in vitro and in vivo models of the neonatal human microbiome. 2. Chickens provide a key source of protein in LMICs, but the chicken gut microbiome acts as a reservoir of AMR that can be transmitted to humans. First, we will develop pilus-dependent lytic phage (PDB) as a tool to eliminate mobile ARGs. Second, we will test the ability of both SSAs and PDBs to control AMR in the chicken gut microbiome using in vivo experiments. Our two-pronged approach will help eliminate AMR from a high-risk patient population and restrict the colonization of humans by decontaminating an important agricultural source of AMR.
- Craig MacLean, University of Oxford, United Kingdom (Coordinator)
- Michael Brockhurst, University of Manchester, United Kingdom (Partner)
- Alvaro San Millan, Centro Nacional de Biotecnología, Spain (Partner)
- Jose Antonio Escudero, Universidad Complutense de Madrid, Spain (Partner)
- Bärbel Stecher-Letsch, Max von Pettenkofer Institute Munich, Germany (Partner)
- Didier Mazel, Institut Pasteur, France (Partner)
- Tao He, Jiangsu Academy of Agricultural Sciences, China (Partner)
Many of the most important one-health AMR genes are carried on mobile genetic elements that move between bacterial strains through the process of conjugation. The genetic mobility of these AMR genes allows them to become widely disseminated across species of bacteria, including harmless commensal strains and dangerous pathogen strains, and ecological niches, including humans, farms and the environment. In our project, we will develop a series of novel interventions to combat these mobile resistance genes. First, we will develop novel genetic tools that will destroy plasmids carrying resistance genes and selectively kill AMR bacteria. In many regions of the world, infants are commonly colonised with AMR bacteria, complicating the treatment of dangerous infections, such as neonatal sepsis. We will test the ability of our genetic tools to eradicate AMR from the neonatal microbiome using experiments in mice containing a microbiome that is typical of human infants. Some phage (viruses that infect bacteria) infect and kill bacteria that carry conjugative plasmids. We will test the ability of these phage to eliminate AMR from the gut microbiome of chickens. Chickens provide a key source of animal protein (global production is about 120 million tonnes per year), but the chickens act as an important source of AMR bacteria that can transfer to humans through food and through the use of chicken manure as a fertiliser. This two pronged approach will allow us to reduce the transmission of AMR to humans and to eliminate AMR from a high risk human population.