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Nutrient-Mediated Delivery of ‘Dual Warhead’ Antimicrobials


Department of Chemistry

About the Project

Background
Microbial resistance to antibiotics is a growing problem. Until recently, antibiotics of the fluoroquinolone-type provided some of the most active broad-spectrum antibacterial agents on the market. However, bacterial resistance to fluoroquinolone antimicrobials is challenging their effectiveness in the clinic.

Novelty
The accepted thought is that fluoroquinolones, such as ciprofloxacin, diffuse into a bacterial cell and are not actively transported. This limits the intracellular concentration that can be achieved and, as a result, their clinical efficacy is lowered.
The use of a chemically modified fluoroquinolone, where a siderophore (a small, high-affinity iron-chelating molecule secreted by bacteria to transport iron across cell membranes) is chemically attached to the fluoroquinolone, has the potential to increase intracellular concentration by delivering the drug through existing active siderophore transporters. Our previous work has shown that conjugation of siderophore to ciprofloxacin via a non-cleavable link impaired ability of the modified ciprofloxacin to inhibit the intracellular drug target (DNA gyrase). This suggests that, after active transport, intracellular release of the fluoroquinolone will preserve antimicrobial activity.

Objectives/Experimental Approach
To design a generic approach allowing chemical modification of current fluoroquinolone drugs to increase intracellular concentrations and overcome permeability and efflux mediated resistance. In addition, judicious chemical modification will allow for a second mode of antimicrobial action to be utilised.

In this project the design of the link between the siderophore transport unit and the fluoroquinolone is such that intracellular cleavage will not only release the fluoroquinolone within the bacterial cytoplasm but the mechanism of cleavage will release a second antimicrobial compound.
These proposed chemical modifications have the potential to deliver an increased concentration of antimicrobial within the bacterial cell. This could lead to lower clinical doses being used, but also provide an alternative killing mechanism against resistant bacterial strains. The lower effective dose could also allow the reassessment of a number of fluoroquinolone antimicrobials that are currently excluded from clinical use due to an unacceptable toxicity profile.

Training
The project is multi-disciplinary and will provide excellent lab-based training since it involves a wide range of techniques including drug design, multistep organic synthesis and biological screening. In addition, the student will take a selection of suitable training courses, which, depending on their background will complement lab-based training. In addition, the successful applicant will gain hands-on expertise in microbiology and biochemistry, in particular antimicrobial activity screening and gyrase inhibition studies.

The student will be provided with a number of other opportunities to network and present their work as a poster or oral presentation both within and external to the University. The student will be encouraged to attend two major international conferences during their PhD. All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/

The candidate must have a background in organic synthesis and be willing to learn the microbiological aspects of the project. You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/.

For more information about the project, click on the supervisor’s name above to email the supervisor. For more information about the application process or funding, please click on email institution


Funding Notes

This project is available to students from any country who can fund their own studies.

The Department of Chemistry at the University of York is pleased to offer Wild Fund Scholarships. Applications are welcomed from those who meet the PhD entry criteria from any country outside the UK. Scholarships will be awarded on supervisor support, academic merit, country of origin, expressed financial need and departmental strategy. For further details and deadlines, please see our website: View Website

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