Self-funded BMS project: Nutrient - Mediated Bacterial Delivery of "Dual Warhead" Antimicrobials

Microbial resistance to antibiotics has been 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.

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.

Current research aims at the chemical modification of current fluoroquinolone drugs to increase intracellular concentrations and overcome permeability and efflux mediated resistance.

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 moiety.

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.

The York Biomedical Research Institute at the University of York is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.

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 programme 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. 

Programme: PhD in Biomedical Science (3 years)

Start Date: 1st October 2022 (the student will be affiliated with the Department of Chemistry)