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Author: Cynthia Michelle Holsclaw
Publisher:
ISBN: 9781124508818
Category :
Languages : en
Pages :
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Book Description
A number of unique metabolites contribute to the virulence of the human pathogen Mycobacterium tuberculosis, the primary causative agent of tuberculosis. Mycobacterium tuberculosis synthesizes a formidable, highly lipid-rich cell envelope, which non-covalently associates with cell surface-exposed lipids specific to pathogenic mycobacteria. Many of these lipids have been linked to the virulence and pathogenesis of the bacterium. However detailing the precise biochemical functions of these metabolites remains an active area of investigation. Determining the detailed chemical structures of these metabolites and elucidating the biosynthetic pathways leading to their production are essential to further our understanding of their specific functions. Therefore, the focus of the research presented in this thesis is to determine the detailed chemical structures and biosynthetic pathways of key Mycobacterium tuberculosis metabolites, as well as to improve the current methodology in the analysis of these compounds. Chapter 1 describes the biology of Mycobacterium tuberculosis and provides a historical background of the investigations into the metabolites further studied in this thesis. This chapter also provides a detailed review of the mass spectrometry techniques essential to the research performed in these studies. Chapter 2 describes the detailed structural characterization of the novel sulfated menaquinone S881, a negative regulator of Mycobacterium tuberculosis virulence. An investigation into the biosynthesis of another cell-surface lipid, polyacyltrehalose, is detailed in Chapter 3. Chapter 4 describes the development of a rapid mass spectrometry-based method to relatively quantitate the mycobacterium-specific redox metabolite mycothiol across different strains of Mycobacterium smegmatis. Finally, Chapter 5 investigates the high-resolution MS analysis of M. tuberculosis cell-surface metabolites, with a focus on the results obtained between two different high-resolution instruments. This study also describes the analysis of S881 levels across five strains of Mycobacterium tuberculosis with differing levels of virulence, as well as the vaccine strain Mycobacterium bovis BCG.
Author: Cynthia Michelle Holsclaw
Publisher:
ISBN: 9781124508818
Category :
Languages : en
Pages :
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Book Description
A number of unique metabolites contribute to the virulence of the human pathogen Mycobacterium tuberculosis, the primary causative agent of tuberculosis. Mycobacterium tuberculosis synthesizes a formidable, highly lipid-rich cell envelope, which non-covalently associates with cell surface-exposed lipids specific to pathogenic mycobacteria. Many of these lipids have been linked to the virulence and pathogenesis of the bacterium. However detailing the precise biochemical functions of these metabolites remains an active area of investigation. Determining the detailed chemical structures of these metabolites and elucidating the biosynthetic pathways leading to their production are essential to further our understanding of their specific functions. Therefore, the focus of the research presented in this thesis is to determine the detailed chemical structures and biosynthetic pathways of key Mycobacterium tuberculosis metabolites, as well as to improve the current methodology in the analysis of these compounds. Chapter 1 describes the biology of Mycobacterium tuberculosis and provides a historical background of the investigations into the metabolites further studied in this thesis. This chapter also provides a detailed review of the mass spectrometry techniques essential to the research performed in these studies. Chapter 2 describes the detailed structural characterization of the novel sulfated menaquinone S881, a negative regulator of Mycobacterium tuberculosis virulence. An investigation into the biosynthesis of another cell-surface lipid, polyacyltrehalose, is detailed in Chapter 3. Chapter 4 describes the development of a rapid mass spectrometry-based method to relatively quantitate the mycobacterium-specific redox metabolite mycothiol across different strains of Mycobacterium smegmatis. Finally, Chapter 5 investigates the high-resolution MS analysis of M. tuberculosis cell-surface metabolites, with a focus on the results obtained between two different high-resolution instruments. This study also describes the analysis of S881 levels across five strains of Mycobacterium tuberculosis with differing levels of virulence, as well as the vaccine strain Mycobacterium bovis BCG.
Author: Graham F. Hatfull
Publisher: John Wiley & Sons
ISBN: 1555818846
Category : Science
Languages : en
Pages : 832
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Book Description
A comprehensive collection of perspectives by experts in mycobacterial molecular biology Mycobacterium tuberculosis causes one in four avoidable deaths in the developing world and kills more adults than malaria, AIDS, and all tropical diseases combined. Tuberculosis was named a global health emergency by the World Health Organization, a distinction no other disease has received. Although the study of mycobacterial genetics has expanded dramatically, with new investigations into mycobacterial growth, replication, metabolism, physiology, drug susceptibility, and virulence, most of the problems in tuberculosis control that existed in 2000 remain today. Advances in our understanding of mycobacterial genetics have been reflected in exciting recent developments. New diagnostic approaches can identify drug resistance within a few hours, promising new drugs are progressing through the pipeline and into the clinic, and a range of newly developed vaccines are being evaluated. It is an exciting time as the fruits of 30 years of intensive genetic investigation are finally beginning to emerge. Written by leading experts in the field, Molecular Genetics of Mycobacteria, Second Edition, Discusses key areas of current research in mycobacterial genetics Explains the genetics of the physiology, metabolism, and drug sensitivities of M. tuberculosis Presents genetic approaches for manipulating M. tuberculosis This book is an invaluable resource for anyone interested in the molecular genetics and molecular biology of mycobacteria.
Author: Sadaf Kalsum
Publisher: Linköping University Electronic Press
ISBN: 9176851540
Category :
Languages : en
Pages : 76
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Book Description
Tuberculosis (TB), an airborne disease and one of the top 10 causes of death globally, is caused by Mycobacterium tuberculosis (Mtb). Current standard therapy for TB treatment includes multiple drugs for a period of at least 6 months. The long therapy duration is to sterilize a small sub-population of drug-tolerant bacteria, a characteristic related to biofilm formation, which otherwise responsible for disease relapse. On the other hand, because of such a long treatment period, patient adherence to therapy becomes difficult, which results in the emergence of multidrug-resistant (MDR) or, in worst cases, extensively drug-resistant (XDR)-TB. TB is primarily a disease of lungs and alveolar macrophages are one of the first host cell types to encounter Mtb following aerosol transmission. A well-established role of macrophages in immune defense is phagocytosis, but recent studies also demonstrated that upon interaction with large aggregates of microbes or cord-forming mycobacterial species, macrophages could produce extracellular traps known as macrophage extracellular traps (METs). METs have a DNA backbone with embeds histones and could trap a wide range of microorganisms, but may or may not be able to kill them. Natural products are always a promising starting point for drug discovery because of their wide range of activity. A large number of world’s population is still using extracts from different parts of plants as the primary source of medicines against diseases including TB. Today much effort is being invested by academia in screening campaigns that allows for fast discovery of new active compounds. Thanks to the use of automated technology such as automated microscopy or automated image analysis (known as high content screening, HCS) phenotypic drug discovery has become easier to perform. Therefore, the identification of highly effective compounds to combat infectious diseases like TB can be facilitated by the use of host-pathogen assays at the early stages of drug screening studies. This thesis describes the characterization and antibiotic sensitivity of different phenotypes of Mtb namely planktonic, cord-forming and biofilm-producing phenotypes that arise due to different culture conditions. The culture of Mtb with a high percentage of a detergent (Tween-80) and standing condition promoted planktonic phenotype while a culture with a low amount of Tween-80 and more aeration due to shaking promoted cording and biofilm phenotypes. Primary human macrophages upon interaction with the shaken culture of wild-type Mtb died by releasing METs. Whereas, the shaken cultures of early secreted antigenic target-6 (ESAT-6), an important virulence factor of Mtb, deletion mutant strain could not induce MET formation showing that the cord formation is related to virulence. Moreover, the biofilm phenotype of Mtb is more tolerant to two first-line antibiotics isoniazid (INH) and rifampicin (RIF) as compared to cording and planktonic phenotypes which demand a search of more effective TB therapy. A screening campaign based on a whole-cell assay using different ethanolic crude extracts of many African plants lead to the discovery of a hit, i.e., a chloroform fraction of Khaya senegalensis bark, which showed non-significant inhibition of intracellular growth of a virulent strain of Mtb was selected for further purification and evaluation. Lastly, we have also developed and validated an HCS assay to explore new compounds against intracellular Mtb in human macrophages. INH and RIF, which were found most effective in our system were used in a combination as a positive control to calculate a Z’ factor value, which confirmed our assay to be suitable for HCS. In conclusion, this thesis not only highlights the biology of TB infection, but also discusses the development of a pathophysiologically relevant assay that can be used in the identification of novel compound(s) that has either direct anti-mycobacterial activity (antibiotic), acts by stimulating the host cell immune mechanisms (immunomodulator) or acts by counteracting virulence factors (virulence blocker).
Author: Barry R. Bloom
Publisher:
ISBN:
Category : Medical
Languages : en
Pages : 664
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Book Description
The authors discuss fundamental questions about the biology, genetics, mechanisms of pathogenicity, mechanisms of resistance, and drug development strategies that are likely to provide important new knowledge about TB and new interventions to prevent and treat this disease.
Author: Kin-Chung Wong
Publisher: Open Dissertation Press
ISBN: 9781374664500
Category :
Languages : en
Pages :
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Book Description
This dissertation, "Molecular Characterization of Mycobacterium Tuberculosis Associated With Phenotypic Virulence in Human Macrophages" by Kin-chung, Wong, 黃建忠, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled "Molecular characterization of Mycobacterium tuberculosis associated with Phenotypic Virulence in human macrophages" Submitted by Wong Kin Chung for the Degree of Doctor of Philosophy at The University of Hong Kong in May 2007 Tuberculosis remains one of the major public health issues in many parts of the world despite the continuous use of live attenuated vaccine. As such, it is essential to conduct thorough studies on its causative agent, Mycobacterium tuberculosis, and the characteristics of its virulence determinants to better understand its microbial pathogenesis. In this present study, clinical isolates of Mycobacterium tuberculosis were studied using insertion sequence IS6110 restriction fragment length polymorphism (RFLP) fingerprinting. Among the 320 isolates collected between 2002 and 2004, IS6110 RFLP revealed that 195 (61%) strains belonged to the Beijing family. To study the bacterial virulence, the intracellular growth of 125 selected strains inside human peripheral blood monocyte-derived macrophages was measured ex-vivo on days 0, 3, 6, and 10. Among all the tested strains, 3 hypervirulent strains showed a significant increase in intracellular growth after 10 days of i 4 incubation. With an initial bacterial load of 10 colony forming unit (CFU), most of the clinical isolates and H37Ra (avirulent control strain) exhibited no intracellular survival of Mycobacterium tuberculosis at day 10, while the 3 hypervirulent strains and H37Rv (virulent control strain) showed an average of 2-4 fold rise in CFU count. These 3 hypervirulent strains belonging to the non-Beijing family were isolated from patients suffering TB meningitis. The cytokines secreted by gamma interferon (IFN-γ) activated macrophage were measured daily until day 5 after the Mycobacterium tuberculosis challenge. Tumor necrosis factor (TNF)-α was elevated after 24 hours of infection among all strains, but (TNF)-α level was significantly lower among the 3 hypervirulent strains . Results were concordant with differential expression of the corresponding cytokine genes in activated macrophages monitored by real-time polymerase chain reaction (PCR). The hypervirulent strains may possess innate mechanisms to resist the host's immunity, accounting for their characteristic virulence and present with a more severe form of disease. This study highlights the advances that aim to better understand epidemiological link, bacterial phenotypic virulence, and interaction with the host's immunity against tuberculosis. ii DOI: 10.5353/th_b3955764 Subjects: Mycobacterium tuberculosis - Molecular aspects Macrophages Molecular epidemiology
Author: Wing-Man Hilda Leong
Publisher: Open Dissertation Press
ISBN: 9781360977089
Category : Medical
Languages : en
Pages : 108
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Book Description
This dissertation, "Molecular Characterization of Virulent Strains of Mycobacterium Tuberculosis" by Wing-man, Hilda, Leong, 梁穎文, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. DOI: 10.5353/th_b4501022 Subjects: Mycobacterium tuberculosis - Molecular aspects
Author: Kin-chung Wong (Ph. D.)
Publisher:
ISBN:
Category : Macrophages
Languages : en
Pages : 208
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Author: Wing-man Leong (Hilda)
Publisher:
ISBN:
Category : Mycobacterium tuberculosis
Languages : en
Pages : 184
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Author: King K. Holmes
Publisher: World Bank Publications
ISBN: 1464805253
Category : Medical
Languages : en
Pages : 1027
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Book Description
Infectious diseases are the leading cause of death globally, particularly among children and young adults. The spread of new pathogens and the threat of antimicrobial resistance pose particular challenges in combating these diseases. Major Infectious Diseases identifies feasible, cost-effective packages of interventions and strategies across delivery platforms to prevent and treat HIV/AIDS, other sexually transmitted infections, tuberculosis, malaria, adult febrile illness, viral hepatitis, and neglected tropical diseases. The volume emphasizes the need to effectively address emerging antimicrobial resistance, strengthen health systems, and increase access to care. The attainable goals are to reduce incidence, develop innovative approaches, and optimize existing tools in resource-constrained settings.
Author: Suzana Anna Savvi
Publisher:
ISBN:
Category : Mycobacterium tuberculosis
Languages : en
Pages : 324
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