Thesis
Investigation into novel antibacterial agents that will bind at GyrA/ParC or GyrB/ParE subunits of DNA gyrase/topoimerase IV
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2019
- Thesis identifier
- T16643
- Person Identifier (Local)
- 201561658
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Due to widespread antibacterial resistance, the urgency to find novel methods of treating multidrug resistant bacteria is greater than ever before. Investigation into novel binding sites on pre-validated drug targets offers one possible new approach to successfully targeting resistant bacteria. Herein, the exploration of two potential alternative binding sites (the NBTI binding site and the ATPase binding site) is discussed. Recent publications have highlighted possible toxicity issues of inhibitors of both sites, and addressing these problems forms the basis for the reported studies. Novel bacterial type II topoisomerase inhibitors (NBTIs) of DNA gyrase subunit A, although well studied within the literature, are commonly found to be potent inhibitors of the human Ether-à-go-go-Related Gene (hERG) channel within the heart. Finding novel methods of alleviating this liability would prompt further investigation and allow the potential use of NBTIs within a clinical setting. An innovative tactic to prevent cardiotoxicity could be through using a soft drug approach. Reported herein are the discoveries of several chemical series with the potential to be optimised into antibacterial soft drugs. One such series has been successfully developed using computational and synthetic studies, prompting the synthesis and characterisation of (S)-REDX10371, an NBTI-type soft drug compound with the antibacterial potency, toxicity and stability profile required to allow in vivo PK properties to be assessed. Inhibitors of DNA gyrase subunit B have also been well investigated. One series of inhibitors has been found to be particularly potent against Mycobacterium tuberculosis, but was observed to be cytotoxic to a hepG2 cell line. Due to the promising nature of the scaffold, further investigation was warranted. Studies surrounding the optimisation of the drug-like properties of a series of GyrB inhibitors were initiated, affording compounds with increased antibacterial activity against both gram-positive and gram-negative pathogens. These studies are presented herein through the enclosure of a short peer-reviewed publication.
- Advisor / supervisor
- Kerr, William
- Resource Type
- Note
- Previously held under moratorium in the Chemistry Department from 13th September 2019 until 22nd March 2023.
- DOI
- Funder
- Embargo Note
Relazioni
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