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Ciprofloxacin Conjugates as Potential Novel Antibiotics

Hardwidge, Peter (2017) Ciprofloxacin Conjugates as Potential Novel Antibiotics. MSc by research thesis, University of York.

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Abstract

Antibiotic resistant bacteria have become a serious threat to modern medicine, as bacteria evolve new ways to counter existing treatments. Fluoroquinolones are an area of great interest for modifications and have been used as a framework for a range of conjugates, however fluoroquinolones can induce phototoxic effects in the patient by the generation of reactive oxygen species (ROS). Phenyl thiourea moieties are known to react with these ROS, thereby alleviating their toxic effect. In this work, the conjugation of ciprofloxacin a selection of substituted phenyl thioureas was investigated with the aim to of determining whether such conjugates could be viable as novel antibiotics whilst protecting against the phototoxic effects of fluoroquinolones. Four of these conjugates were successfully synthesised and screened against the BW25113 strain of E. coli. However, the conjugates were observed to have a higher MIC, i.e. lower antimicrobial activity, than ciprofloxacin. To probe if the drop in antimicrobial activity correlates with a decrease in the affinity of the conjugate for the drug target, DNA gyrase, a DNA gyrase binding assay was carried out. It was observed that the binding affinity of the conjugate had decreased. It was therefore concluded that the attachment of a thiourea moiety to ciprofloxacin decreases the DNA gyrase inhibitory activity of the parent drug, ciprofloxacin. As an extension a study was undertaken into the use of a biolabile disulfide linker between the two moieties to investigate whether it would be suitable as a delivery mechanism for a ciprofloxacin thiourea conjugate. The initial synthetic target was a dimer of ciprofloxacin linked with a disulfide bridge, to allow the assessment of the disulfide. Screening of this molecule showed that the disulfide link was increasing the MIC compared to the monomer of ciprofloxacin.

Item Type: Thesis (MSc by research)
Academic Units: The University of York > Chemistry (York)
Depositing User: Mr Peter Hardwidge
Date Deposited: 11 Jun 2018 08:49
Last Modified: 11 Jun 2018 08:49
URI: http://etheses.whiterose.ac.uk/id/eprint/19662

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