Satta, Giovanni;
(2018)
The challenge of drug resistant tuberculosis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Tuberculosis remains a major cause of morbidity and mortality globally with 10.4 million new cases worldwide in 2015 (WHO data). Drug resistance has also emerged as a public health concern in high-income countries as a result of immigration from endemic areas, the HIV pandemic and immunosuppressive treatments. The challenge this expansion poses to public health authorities is illustrated by an outbreak of isoniazid resistant tuberculosis in London (UK) in which over 400 cases have been diagnosed since 1995. The main scope of this thesis is to address the challenges of drug resistant tuberculosis, with a particular focus on the applications of whole genome sequencing to the drug discovery process. A multi-strategy approach has been adopted, starting with the use of next generation sequencing to understand pathogenicity and discover new potential drug targets, to the laboratory testing of new compounds. Using a sub-cluster of strains from the London outbreak, our findings have confirmed the utility of whole genome sequencing in understanding the pathogenesis of clinical strains, discovering specific genetic mutations that may have allowed the outbreak to persist for years. At the same time, we have also integrated sequencing technologies within the screening process of new compounds and we have demonstrated its potential role in elucidating the mechanism of action of old and new drugs, in particular para-aminosalicylic acid and its newly created analogues. The repurposing of current drugs (carbapenems) has been evaluated as a potential treatment in case of drug resistance whilst gold nanoparticles have been assessed as alternative compounds. Hence, this thesis has reflected the complexity of addressing the challenge of drug resistant tuberculosis and how a multi strategy approach is essential for the eradication of this global pathogen.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The challenge of drug resistant tuberculosis |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. Third party copyright material has been removed from ethesis. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10064520 |
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