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Investigating the Mitotoxicity of Fluoroquinolone Antibiotics


   School of Pharmacy and Biomedical Sciences

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Applications are invited for a self-funded, 3 year full-time or 6 year part-time PhD project.

The PhD will be based in the School of Pharmacy and Biomedical Science and will be supervised by Dr Robert Baldock. 

The work on this project will:

Examine the cellular and molecular impact of fluoroquinolone antibiotics and characterise their impact on mitochondrial function. 

Uncover and catalogue the potential DNA repair mechanisms that protect and repair mitochondrial DNA

Project details:

Antibiotics are the most fundamental tools we have in the fight against bacterial infections. Without these drugs, bacterial infections that could otherwise be easily treatable could become life-threatening, as such it has become essential to ensure that these drugs can continue to be used and remain effective. Recently, a group of antibiotics, known as fluoroquinolones, have been shown to cause number of severe and potentially permanent disabling side-effects in a sub-population of the people who are prescribed them. This has resulted in the use of these highly-effective antibiotics being restricted due to the potential side-effects. Further research has demonstrated that the side-effects of fluoroquinolones result from off-target effects in mitochondria in some patients, though it is unclear why some individuals suffer these side-effects while others do not.

This research aims to establish why some individuals suffer from these severe side-effects by investigating the mechanisms employed by cells to protect their mitochondrial DNA. By understanding this process, it will potentially be possible to screen-out individuals who are likely to suffer these adverse effects before prescribing. Importantly, having this approach would ensure that these drugs can continue to be used safely.

This project will employ mammalian cell culture alongside the establishment of several cell-based assays to examine the cells and the mitochondria via microscopy, flow cytometry and plate-reader based assays. In addition, the mitochondrial DNA copy number will be examined directly using quantitative PCR. Previously, our lab has identified several candidate DNA repair proteins that are part of the mitochondrial proteome (Alkanjari & Baldock, 2021. Bioscience Reports). By examining changes in mitochondrial function of cells depleted of these factors in response to mitotoxic stress, we will determine which proteins contribute to the protection and repair of mitochondrial DNA. There will also be opportunities for the PhD candidate to develop highly transferable skills including coding and several bioinformatic methods. 


References

Allkanjari K. & Baldock R.A. (2021) “Beyond base excision repair: An evolving picture of mitochondrial DNA repair” Bioscience Reports, Vol. 41(10): BSR20211320.

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