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Title: Exploiting bacterial transporters for the design of novel antibacterial agents
Author: Carrick, Christopher
ISNI:       0000 0004 5348 853X
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2014
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The alarming increase in the occurrence of antimicrobial resistance has led to a situation whereby some strains are untreatable by known antimicrobials. The Trojan horse strategy is one methodology with the potential to overcome the rising tide of resistance. Work was undertaken to synthesise two different Trojan horses. One based on an analogue of the Bacillus siderophore petrobactin, the other a novel compound prepared using the Ugi four component condensation. Both contained a fluoroquinolone antimicrobial; ciprofloxacin. Additionally a series of bis-catecholate ligands were prepared for use as iron chelating antimicrobial agents. The Trojan horse based on the Ugi four component condensation was screened against wild type E. coli and was found to have antibacterial activity, but at a lower level than the parent drug ciprofloxacin. The mechanism of action was determined by performing a DNA gyrase assay, which confirmed the conjugate was inhibiting E. coli DNA gyrase activity. A set of three glycosylated fluoroquinolones was screened, to assess the extent to which they were actively transported. Experiments were performed using glucose and galactose as carbon sources, with E. coli strains deficient in galactose transport. Further experiments with outer membrane porins (OMPs) mutants were also performed. The results suggested that the conjugates were not actively transported, but were gaining access to the cells via the OMPs. Studies were undertaken on the bis-catecholate ligands to assess their suitability as potential antimicrobial agents. However, stability studies showed that one set of ligands was highly unstable due to hydrolysis and oxidation, and therefore not viable for use. The asymmetric ligand showed promising activity in vitro however electrochemical studies indicated it was susceptible to oxidation. Consequently, the active species could not be reliably determined. Further study is required to establish its identity.
Supervisor: Routledge, Anne ; Duhme-Klair, Anne-Kathrin ; Thomas, Gavin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available