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Characterising Tuberculosis and Treatment Failure Thereof Using Metabolomics

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Characterising Tuberculosis and Treatment Failure Thereof Using Metabolomics Characterising tuberculosis and treatment failure thereof using metabolomics L Luies 21637156 Thesis submitted for the degree Philosophiae Doctor in Biochemistry at the Potchefstroom Campus of the North-West University Promoter: Prof Du Toit Loots April 2017 "In science one tries to tell people, in such a way as to be understood by everyone, something that no one ever knew before." Paul Dirac ACKNOWLEDGEMENTS The contributions of the following institutions and individuals made towards the successful completion of this study are hereby acknowledged: NRF/DST Centre of Excellence in Biomedical Tuberculosis Research, Faculty of Health Sciences, University of Stellenbosch, South Africa, for providing the urine samples used in this investigation. The National Research Foundation (NRF) of South Africa, Technology Innovation Agency (TIA) and North-West University (NWU) for the research grants provided. Prof. Du Toit Loots, my study supervisor, and other members of the NWU Biochemistry Department (especially Prof. Japie Mienie, Dr. Ilse du Preez, Mrs. Mari van Reenen, Mrs. Derylize Beukes-Maasdorp and Dr. Zander Lindeque), for their guidance, expertise, insights, advice and patience throughout the years. My friends, for the moments of laughter and stress relief, which has kept me sane. My dearest parents, Leonard and Sandra, for their unending love, prayers, mental encouragement and financial support during my studies. My husband, Juan, for all your love, support and encouragement, every step of the way. “I can do everything though Christ who gives me strength.” Philippians 4:13 i TABLE OF CONTENTS ACKNOWLEDGEMENTS ....................................................................................................... i SUMMARY ............................................................................................................................ vi LIST OF TABLES ............................................................................................................... viii LIST OF FIGURES ................................................................................................................. x LIST OF SYMBOLS AND ABBREVIATIONS ...................................................................... xii CHAPTER 1: PREFACE ........................................................................................................ 1 1.1 BACKGROUND AND MOTIVATION ................................................................. 1 1.2 AIMS AND OBJECTIVES OF THIS STUDY ...................................................... 2 1.2.1 Aims ................................................................................................................. 2 1.2.2 Objectives ......................................................................................................... 3 1.3 STRUCTURE OF THESIS AND RESEARCH OUTPUTS ................................. 3 1.4 AUTHOR CONTRIBUTIONS ............................................................................ 5 1.5 REFERENCES ................................................................................................. 7 CHAPTER 2: LITERATURE REVIEW ................................................................................... 8 2.1 METABOLOMICS ............................................................................................. 8 2.2 M. TUBERCULOSIS BACTERIOLOGY AND PATHOPHYSIOLOGY.............. 11 2.2.1 The M. tuberculosis cell wall ........................................................................... 11 2.2.2 Transmission and pathogenicity ...................................................................... 13 2.3 TUBERCULOSIS DIAGNOSTICS ................................................................... 16 2.3.1 Diagnosing latent M. tuberculosis infection ..................................................... 16 2.3.1.1 Tuberculin skin test .................................................................................... 16 2.3.1.2 Interferon gamma release assays .............................................................. 17 2.3.2 Diagnosing active M. tuberculosis infection ..................................................... 18 2.3.2.1 Microscopy smear techniques .................................................................... 18 2.3.2.2 Bacteriological cultures............................................................................... 18 2.3.2.3 Nucleic acid amplification techniques ......................................................... 19 2.3.2.4 Serological (immunological) methods ......................................................... 20 2.3.2.5 Phage-based assay .................................................................................... 21 2.3.3 Metabolomics biomarkers for tuberculosis diagnostics .................................... 21 2.3.3.1 Metabolomics biomarkers detected using Mycobacterium cultures ............ 22 2.3.3.2 Metabolomics biomarkers detected using sputum ...................................... 26 2.3.3.3 Metabolomics biomarkers detected using blood and tissue ........................ 28 ii 2.3.3.4 Metabolomics biomarkers detected using urine .......................................... 32 2.3.3.5 Metabolomics biomarkers detected using breath ........................................ 33 2.3.3.6 Diagnostic validity of the metabolomics tuberculosis biomarkers identified to date ............................................................................................................ 35 2.3.3.7 From benchtop to clinical application: Future prospects and challenges of metabolomics biomarkers ........................................................................... 38 2.4 TUBERCULOSIS TREATMENT ..................................................................... 39 2.4.1 Isoniazid ......................................................................................................... 40 2.4.2 Rifampicin ....................................................................................................... 41 2.4.3 Pyrazinamide .................................................................................................. 42 2.4.4 Ethambutol ..................................................................................................... 43 2.4.5 Using metabolomics to better explain anti-tuberculosis drug action and drug metabolism ..................................................................................................... 44 2.5 TUBERCULOSIS TREATMENT FAILURE...................................................... 46 2.5.1 Variable individual metabolism ........................................................................ 47 2.5.1.1 Xenobiotic metabolism ............................................................................... 47 2.5.1.2 Drug malabsorption .................................................................................... 49 2.5.1.3 Drug-drug interactions ................................................................................ 50 2.5.2 Drug-resistance and pathogenicity by the infectious organism ........................ 53 2.5.3 Non-adherence due to the associated side-effects.......................................... 57 2.6 PREDICTING TUBERCULOSIS TREATMENT OUTCOME ............................ 59 2.7 REFERENCES ............................................................................................... 62 CHAPTER 3: METABOLOMICS METHODOLOGY AND REPEATABILITY ....................... 75 3.1 INTRODUCTION ............................................................................................ 75 3.2 EXPERIMENTAL DESIGN .............................................................................. 76 3.3 MATERIALS AND METHODS ........................................................................ 77 3.3.1 Urine sample collection and storage ............................................................... 77 3.3.1.1 Quality control samples .............................................................................. 78 3.3.2 Reagents and chemicals ................................................................................. 78 3.3.3 Organic acid extraction procedure and derivatisation ...................................... 79 3.3.4 GCxGC-TOFMS analyses ............................................................................... 79 3.3.5 Data processing .............................................................................................. 80 3.3.6 Batch effect ..................................................................................................... 80 3.4 RESULTS AND DISCUSSION ........................................................................ 82 3.4.1 Repeatability ................................................................................................... 82 3.5 CONCLUSION ................................................................................................ 84 3.6 REFERENCES ............................................................................................... 84 iii CHAPTER 4: ADAPTATIONS OF MAN AND MICROBE IN ORDER TO OUTCOMPETE AND SURVIVE ..................................................................................................................... 85 4.1 ABSTRACT..................................................................................................... 85 4.2 INTRODUCTION ............................................................................................ 86 4.3 MATERIALS AND METHODS .......................................................................
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