About the Project
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.
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