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dc.contributor.advisorQuinn, Ronald J
dc.contributor.authorXie, Yan
dc.date.accessioned2021-09-03T05:41:19Z
dc.date.available2021-09-03T05:41:19Z
dc.date.issued2021-08-18
dc.identifier.doi10.25904/1912/4318
dc.identifier.urihttp://hdl.handle.net/10072/407560
dc.description.abstractTuberculosis (TB) is the number one cause of human death from infectious disease in the world. Current treatments are challenged by the high levels of drug-resistant Mtb infection, which including rifampicin-resistant TB (RR-TB), multidrug-resistant TB (MDR-TB), and extensively drug resistant TB (XDR-TB). New drugs with mechanism of action (MOA) are required for more effective treatments. The literature review covered TB disease, the discovery of current treatments and clinic candidates, natural products in TB drugs, two drug discovery strategies phenotypic based drug discovery (PDD) and target based drug discovery (TDD), and a platform to directly observe protein-ligand complexes. A combination of phenotypic screening with NMR fingerprints led to the isolation kokusaginine (2.1) from Flindersia maculosa Lindl. , a mixture of flindersiamine (2.2) and maculine (2.3) from Flindersia maculosa Lindl., fascaplysin (2.4) from Fascaplysinopsis sp., and agelasine D (2.5) from Agelas axifera. Fascaplysin (2.4) and agelasine D (2.5) showed strong inhibitory activities against M. smegmatis. Data analysis of phenotypic screening and molecular target screening prioritised four PFs fractions for identification of the active constituents. Polycarpine (4.1) from the marine organism, Polycarpa aurata, formed a covalent bond with Rv1466. Polycarpine (4.1) had a pseudo-KD as 5.3 ± 0.4 μM with Rv1466. Rv1466 (5IRD) has a single cysteine that is exposed on the surface of the protein Polycarpaurine C (4.2) was also identified as a covalent ligand bound to Rv1466. Isogoyazensolide (5.1) and goyazensolide (5.3), and one new compound (5.2) were isolated from Centratherum sp.. Both isogoyazensolide (5.1) and goyazensolide (5.3) formed protein-ligand complexes with Rv1466 but the binding affinities were weak. Given the reported anti-TB activity of isogoyazensolide (5.1) and goyazensolide (5.3) against Mtb H37Ra, Rv1466 is likely NOT the target. Five compounds, dibromophakellin (6.1), (10Z)-debromohymenialdisine (6.2), aldisin (6.3), 2-bromoaldisin (6.4), and stylisine A (6.5) were isolated from Stylissa flabellate Dibromophakellin (6.1) interacted with Rv3606c while the other four compounds did not. The similar binding affinities of dibromophakellin (6.1) with Rv3606c from M. fortuitum and M. abscessus. indicated that Rv3606c as a drug target in M. fortuitum and M. abscessus. Analysis of the chemical constituents and biological activities of an ethnic medicine, Ardisia japonica, used to treat TB in China gave a PhenoTarget correlation map of isolated compounds, the traditional application, cell-based phenotypes and molecular targets. The advantages and disadvantages of the novel PhenoTarget approach are discussed relative to the overall aim to combine PDD and TDD to identify the compounds with anti-TB activities.
dc.languageEnglish
dc.language.isoen
dc.publisherGriffith University
dc.publisher.placeBrisbane
dc.subject.keywordsTuberculosis
dc.subject.keywordsTB
dc.subject.keywordsRifampicin-resistant
dc.subject.keywordsMultidrug-resistant
dc.subject.keywordsExtensively drug resistant
dc.subject.keywordsMechanism of action
dc.subject.keywordsDrugs
dc.subject.keywordsPhenoTarget
dc.titleA PhenoTarget Approach for Identifying Bioactive Compounds that Interact with TB Proteins
dc.typeGriffith thesis
gro.facultyScience, Environment, Engineering and Technology
gro.rights.copyrightThe author owns the copyright in this thesis, unless stated otherwise.
gro.hasfulltextFull Text
dc.contributor.otheradvisorFeng, Yun J
dc.contributor.otheradvisorDeng, Jiagang
dc.contributor.otheradvisorHou, Xiaotao
dc.contributor.otheradvisorLiu, Miaomiao
gro.identifier.gurtID000000023010
gro.thesis.degreelevelThesis (PhD Doctorate)
gro.thesis.degreeprogramDoctor of Philosophy (PhD)
gro.departmentSchool of Environment and Sc
gro.griffith.authorXie, Yan


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