Repositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activity

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dc.contributor.advisorChibale, Kellyen_ZA
dc.contributor.advisorWarner, Digby Fen_ZA
dc.contributor.authorWasuna, Antoninaen_ZA
dc.date.accessioned2018-05-25T07:49:38Z
dc.date.available2018-05-25T07:49:38Z
dc.date.issued2018en_ZA
dc.description.abstractTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death globally, especially in low and middle-income countries. TB is primarily a curable disease, with chemotherapy predicated on a combination of four drugs. The increase in multiple forms of drug-resistant TB is a major cause for concern, underpinning the importance of a continuous pipeline of new anti-TB agents. Drug repositioning - that is, the optimization of existing drugs for new therapeutic indications - has shown promise in expanding the therapeutic options for TB chemotherapy. Fusidic acid (FA), a natural product-derived antibiotic, has modest in vitro antimycobacterial activity. Through a multi-disciplinary approach combining aspects of chemistry and biology, this study investigated the pharmacological and physicochemical properties of FA that might be exploited for optimization of FA as a lead compound for TB drug discovery. FA is a weak carboxylic acid, and it was hypothesised that the carboxylic acid moiety limits its permeation of the complex mycobacterial cell wall. Therefore, this study aimed to identify novel FA analogues with improved permeation properties and designed to act as potential prodrugs. By modifying the C-3 hydroxyl and the carboxylic acid moiety, alkyl and aminoquinoline derivatives were covalently fused to FA through ester and amide coupling reactions to generate hybrids and/or potential prodrugs.en_ZA
dc.identifier.apacitationWasuna, A. (2018). <i>Repositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activity</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/28154en_ZA
dc.identifier.chicagocitationWasuna, Antonina. <i>"Repositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activity."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2018. http://hdl.handle.net/11427/28154en_ZA
dc.identifier.citationWasuna, A. 2018. Repositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activity. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Wasuna, Antonina AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death globally, especially in low and middle-income countries. TB is primarily a curable disease, with chemotherapy predicated on a combination of four drugs. The increase in multiple forms of drug-resistant TB is a major cause for concern, underpinning the importance of a continuous pipeline of new anti-TB agents. Drug repositioning - that is, the optimization of existing drugs for new therapeutic indications - has shown promise in expanding the therapeutic options for TB chemotherapy. Fusidic acid (FA), a natural product-derived antibiotic, has modest in vitro antimycobacterial activity. Through a multi-disciplinary approach combining aspects of chemistry and biology, this study investigated the pharmacological and physicochemical properties of FA that might be exploited for optimization of FA as a lead compound for TB drug discovery. FA is a weak carboxylic acid, and it was hypothesised that the carboxylic acid moiety limits its permeation of the complex mycobacterial cell wall. Therefore, this study aimed to identify novel FA analogues with improved permeation properties and designed to act as potential prodrugs. By modifying the C-3 hydroxyl and the carboxylic acid moiety, alkyl and aminoquinoline derivatives were covalently fused to FA through ester and amide coupling reactions to generate hybrids and/or potential prodrugs. DA - 2018 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2018 T1 - Repositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activity TI - Repositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activity UR - http://hdl.handle.net/11427/28154 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/28154
dc.identifier.vancouvercitationWasuna A. Repositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activity. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2018 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/28154en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherChemistryen_ZA
dc.subject.otherTB chemotherapyen_ZA
dc.subject.otheranti-TB agentsen_ZA
dc.titleRepositioning fusidic acid for tuberculosis: semi-synthesis of analogues and impact of mycobacterial biotransformation on antibiotic activityen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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