The evolutionary emergence of multidrug resistant bacterial pathogens

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Increasing antibiotic resistance in bacterial infections is a serious threat to modern medicine, so understanding why some bacteria become resistant to multiple antibiotics whereas others do not is an important challenge for microbiologists, doctors and vets. In pathogenic E. coli - the most common cause of blood and urine infections worldwide and recognised by the World Health Organisation as a top global health threat - antibiotic resistance is associated with gaining extra loops of DNA called plasmids that carry several different antibiotic resistance genes. Not all E. coli strains seem to be able to maintain such plasmids, which is probably because gaining plasmids is typically very costly because the genes the plasmids carry interfere with the workings of the bacterial cell. Our work has led us to hypothesise that this variation between strains of E. coli is due to differences in how the various strains regulate the expression of their genes allowing some to mitigate for the disruption caused to the cell by the plasmid. In this project we will test this idea in the laboratory using evolution experiments and cutting-edge sequencing technology. We have gathered together a collection of plasmid-free E. coli strains whose close relatives do typically carry antibiotic resistance plasmids in nature. First, we will compare the costs of acquiring a plasmid and the level of antibiotic resistance provided in both types of strain. We predict that costs will be higher in strains that don't typically carry plasmids. Second, we will compare the disruption caused to the cell by acquiring a plasmid in both types of strain by measuring patterns of how they express their genes. We predict that disruption to the cell caused by gaining the plasmid will be greater in strains that don't typically carry plasmids, and that this will scale with the costs we measure of carrying the plasmid. Third, we will experimentally evolve bacteria carrying plasmids in the lab to observe in real time how natural selection compensates for the cost of acquiring a plasmid. We predict that evolved bacteria will gain new mutations in regulators that turn genes on or off, to mitigate the disruption to the cell caused by carrying a plasmid, and that this process will be faster and more efficient in strains that typically carry plasmids. Fourth, we will test how the mutations observed during experimental evolution affect the expression of genes in cells with and without plasmids, to understand the molecular mechanisms by which evolution allows bacteria to maintain plasmids. This project will advance our fundamental understanding of how and why pathogenic strains of E. coli that are highly resistant to antibiotics evolve. In future this insight could help us to identify potential superbugs before they emerge, or suggest novel targets for drugs that force bacteria to lose their antibiotic resistance plasmids making them susceptible to conventional treatments.