The evolutionary ecology of plasmid-mediated horizontal gene transfer in the hospital sink drain ecosystem

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Antimicrobial resistance (AMR) in opportunistic pathogens represents a major emerging threat to modern medicine. A world of difficult-to-treat opportunistic infections impacts health outcomes both in terms of the direct burden of infections, and the broader effects on quality of life if elective procedures become too dangerous. AMR often emerges when bacteria acquire pieces of DNA known as plasmids from their neighbours. Plasmid transmission can occur outside of an infection setting and without antibiotic selection, so many opportunistic pathogens acquire AMR in their normal habitats before they have the chance to cause infection. However, the ability of bacteria to carry plasmids can vary, with some species or strains better at carrying and spreading plasmids than others. Understanding plasmid biology in the context of bacterial communities is therefore crucial to predicting and controlling AMR in opportunistic pathogens.Sinks on hospital wards are a key habitat in which clinically-impactful AMR emergence can occur. Bacteria are dispersed from sinks by droplets and aerosols, and genomic surveillance has implicated sinks as point sources of AMR outbreaks. Sinks are often located close to high antimicrobial usage environments, which can provide a source of resistant bacteria, and to infections, which can provide a source of dangerous pathogens. Sinks sustain robust, long-lasting multispecies biofilms, which favour close interactions that promote plasmid transmission. Sinks are also frequently treated with chemicals that can act both as a direct trigger of plasmid conjugation and select for plasmids that carry disinfectant resistance alongside AMR. However, the unique ecosystem of the ward sink has often been overlooked in studies of AMR in favour of animal models. In this project I will directly investigate the evolutionary and ecological drivers of plasmid transmission in the sink microbial ecosystem. I will focus on Pseudomonas aeruginosa - a common inhabitant of sinks, a major cause of opportunistic infection, and a 'critical priority' for AMR research (World Health Organisation, 2017) because without effective antibiotics, Pseudomonas infections can be very difficult to control.My previous work with Pseudomonas identified and characterised a widespread family of plasmids responsible for AMR, but I have also shown that the ability of Pseudomonas to carry plasmids varies widely between different species and strains. Building on this work, here I will test the hypothesis that some Pseudomonas act as plasmid 'reservoirs', driving transmission of AMR to pathogens in the sink drain ecosystem. I have four objectives:1.Explore plasmid transmission in real-world sinks on an experimental hospital ward and determine how these patterns are affected by chemical disinfection, using innovative metagenomics that can track plasmid transfer across whole communities.2.Investigate the biology of Pseudomonas plasmid 'reservoirs' by testing how different species and strains respond when they acquire a new plasmid.3.Investigate how plasmid reservoirs evolve, by determining the genome changes associated with plasmid carriage across almost 100 strains.4.Determine the role of plasmid 'reservoirs' in experimental sink drain communities, and measure their contribution to AMR persistence.Together these experiments will establish the ecological features of AMR emergence in a priority pathogen, in an infection-relevant environmental habitat. In the process, this project will reveal general principles of plasmid-bacterial interactions and microbial ecology that will inform future interventions to limit AMR emergence.