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Targeting antibiotic resistance in bacteria: the importance of genome segregation


Project Description

Bacterial antibiotic resistance is a growing problem worldwide. The latter half of the twentieth century has witnessed the dissemination of multidrug-resistant bacteria. The emergence of multidrug-resistant ‘superbugs’ among bacterial populations results either from mutations within the bacterial genome or from the horizontal transfer of resistance genes often present on mobile genetic elements such as plasmids, bacteriophages, transposons and pathogenicity islands.

Low-copy number plasmids responsible for antibiotic resistance employ sophisticated strategies to ensure faithful distribution at cell division. These plasmids encode two proteins, an ATPase and a DNA-binding protein, which assemble into a minimalist DNA segregation machine. This protein complex interfaces with the nucleoid and drives the plasmids to defined subcellular addresses. When this systems malfunctions, the plasmid is lost, resulting in a bacterial population sensitive to antibiotics.

Our model system is the TP228 plasmid, which replicates at low copy number in Escherichia coli. It specifies resistance to a range of antibiotics such as tetracycline, streptomycin, kanamycin, neomycin, spectinomycin and sulphonamides. The plasmid partition cassette encodes two proteins, an ATPase and a DNA-binding protein, that form a complex responsible for maintaining the plasmid in the cell. We have proposed a Venus flytrap model as a mechanism for plasmid segregation (1). This model predicts that the plasmid is retained by being entrapped within a matrix formed by one of the partition proteins; exclusion from the matrix results in plasmid loss.

This project will investigate the cellular localization of segregation protein complexes and the dynamics of complex assembly at single molecule level. The experimental approaches will include:
1. Molecular biology and genomic techniques such as Chip-seq and Hi-C;
2. Microscopy, including high-resolution Slimfield microscopy (2) to track proteins within the cell;
3. Biochemical and biophysical techniques: such as ensemble and single-molecule protein-protein interaction tools and Atomic Force Microscopy.

Funding Notes

This is a BBSRC WR DTP studentship fully-funded for 4 years and covers: (i) a tax-free stipend at the standard Research Council rate (around £15,000 per year) (ii) research costs, and (iii) tuition fees at the UK/EU rate. The studentship is available to UK and EU students who meet the UK residency requirement (to have been residing in the UK for at least 3 years continuously prior to the start of the PhD).

References

ENTRY REQUIREMENTS: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions.

How good is research at University of York in Biological Sciences?

FTE Category A staff submitted: 44.37

Research output data provided by the Research Excellence Framework (REF)

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