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Nutrient-Mediated Delivery of ‘Dual Warhead’ Antimicrobials


Department of Chemistry

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Dr A Routledge , Prof A-K Duhme-Klair Applications accepted all year round

About the Project

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 the fluoroquinolones is now challenging their clinical effectiveness. The accepted thought is that fluoroquinolones such as ciprofloxacin diffuse into the cell and are not actively transported. This limits the intracellular concentration that can be achieved.

Research Goal- 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.

Use of modified fluoroquinolone antimicrobials, where a siderophore is chemically attached to the fluoroquinolone, has the potential to increase intracellular concentration by delivering the drug through existing active transporters. Our previous work has shown that conjugation via a non-cleavable link impaired ability of modified ciprofloxacin to inhibit the intracellular drug target (DNA gyrase). This suggests that, after active transport, intracellular release of the fluoroquinolone will improve activity. The design of the link between the siderophore transport unit and the fluoroquinolone is such that intracellular cleavage will not only release the fluoroquinolone but the mechanism of cleavage will release a second antimicrobial.

The chemical modifications would allow an increased concentration of antimicrobials to be achieved within bacterial cells. This could lead to lower clinical doses being used, but also provide an alternative killing mechanism against bacteria that show resistance. 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.

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 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/.

You should expect 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/

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: https://www.york.ac.uk/chemistry/postgraduate/research/funding/wild/
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