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Structurally guided drug design on new antibiotics targeting DNA gyrase


   Cardiff School of Biosciences

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  Dr Ben Bax, Prof S Ward  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Background

Antibiotic resistance is a huge problem in the field of antibacterial drugs, and much research is focused on the development of new drugs to overcome this. One of the most successful classes of drugs are quinolones, which target DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. Today two novel classes of compounds that target DNA gyrase (and topo IV) are in phase III clinical development trials.

Project Description

This project will focus on crystallographic studies of S. aureus DNA-gyrase complexed with DNA, and with the drug zoliflodacin. The project will aim to answer the question 'Is zoliflodacin an effective drug because it binds to several different DNA-cleavage conformations with DNA Gyrase"¶ (1) and will aim to provide a structural platform to replace quinolones with spirocyclic quinoline barbituric acids, (which may well have better safety profiles than fluoroquinolones).

This project aims to assist these developments by using state of the art instrumentation at Diamond to aid in the structural investigation of these complexes. Understanding the binding properties will help in the development of related drugs which overcome issues of quinolone target-related drug resistance. The state of the art beamline, VMXm will be used due to its micro/nanofocus beamsize (0.3 x 2.5um) to allow these highly challenging crystals to be investigated. There will also be the ability to use electron diffraction to study the challenging samples. The project will extend diffraction studies by carrying out fragment screens using XChem for both conventional and micro-crystals. This project will be highly collaborative in nature, bringing together teams from the Medicines Discovery Institute at Cardiff University and Diamond.

Additional Note

The appointed candidate will be required to sign an Appointment Agreement with the University and Diamond in advance of commencing the studentship. A copy of the Appointment Agreement will be set out and the student will be required to sign a Studentship Agreement. The student should be informed as to why such an agreement is required and advised that whilst he/she is not obligated to sign, if they do not wish to do so, they will not be able to accept this particular studentship offering. The student should be advised that he/she is entitled to seek independent legal advice if desired.

Start date

This studentship will commence on 1st April 2022.

How to apply

In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the application system, click the ’Visit Institution’ button on this advert). There is a box at the top right of the page labelled ‘Apply’ - please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (April 2022). This will take you to the application portal.

In the research proposal section of your application, please specify the project title and supervisors of this project and copy the project description in the text box provided. In the funding section, please select 'I will be applying for a scholarship/grant' and specify that you are applying for advertised funding.

Interviews

If your application is shortlisted for interview, you will be contacted and an interview will be arranged for the week commencing 28th February.


Funding Notes

Funding only covers Home UK student fees. EU and International Students may apply but will need to cover the difference between Home UK and International fees.
Funding from Diamond Light Source will cover Home rate tuition fees (4 years), Stipend (£73,620 over 4 years), Consumables, Conf.& Travel.

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