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Probing a DNA segregation machine at single molecule level to combat antibiotic resistance


Project Description

Bacterial multidrug resistance is a global burden on human health worldwide.
Large, low copy number plasmids responsible for antibiotic resistance have
evolved strategies to ensure their faithful distribution at cell division. Multidrug resistance plasmids harbour their own survival system, a two-gene partition cassette, which ensures accurate segregation of the plasmids at cell division. When this system malfunctions, the plasmid is not stably inherited and is ultimately lost, causing bacteria to become sensitive to antimicrobials. The multidrug resistance plasmid TP228 replicates at low copy number in Escherichia coli. Its partition cassette encodes two proteins: ParF, an ATPase, and ParG, a DNA-binding protein that associates to a specific site on the plasmid. By using super-resolution microscopy on live cells, we have shown that ParG-plasmid complexes are entrapped within a three-dimensional ParF matrix that assembles through the volume of the bacterial chromosome. When the ParG protein is defective, the ParG-plasmid complex is not associated to the chromosome and lost at the following cell division. We have proposed a Venus flytrap model as a mechanism for plasmid segregation (1).

This project will investigate the localization of ParFG-plasmid complexes in the cell and the dynamics of complex formation at single molecule level to shed light on the mechanism underpinning the segregation of plasmids responsible for multiple antibiotic resistance. The study will involve molecular biology and super-resolution fluorescence microscopy (2) in parallel to biochemical approaches to visualize proteins and plasmid positioning within bacterial cells.

1. McLeod B, Allison-Gamble GE, Barge MT, Tonthat NK, Schumacher MA,
Hayes F, Barillà D (2017) A three-dimensional ParF meshwork assembles
through the nucleoid to mediate plasmid segregation. Nucleic Acids Res 45,
3158-3171
2. Syeda A, Wollman AJM, Hargreaves AL, Howard J, Brüning J-L, McGlynn P, Leake MC (2019) Single-molecule live cell imaging of Rep reveals the dynamic interplay between an accessory replicative helicase and the replisome. Nucleic Acid Res (in Press) DOI: 10.1093/nar/gkz298

Funding Notes

This studentship is fully funded for four years and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,009 estimated for 2020 entry), (ii) research costs, and (iii) tuition fees at the UK/EU rate.

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 research project 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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