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EPFL

1. Sommer, Raphael Christopher. Innovative Tools and in vivo Methods for Tuberculosis Drug Discovery and Development.

Degree: 2019, EPFL

Worldwide, tuberculosis (TB) is the leading cause of death due to a single infectious agent, claiming 1.6 million human lives and causing >10 million new cases in 2017 alone, mostly in low-income regions. The intracellular pathogen Mycobacterium tuberculosis is the etiological agent and generally infects the lungs. Although treatments exist, curing TB requires long and often expensive chemotherapy, frequently accompanied by undesirable side-effects. In the absence of an effective vaccine and with the increasing emergence of multidrug resistance, new and more powerful antibiotics are urgently needed to control the global TB crisis. In this respect, benzothiazinones (BTZs), a class of new anti-TB compounds, have recently been discovered. Macozinone (PBTZ169), that has reached phase I and II clinical trials in Switzerland and Russia, respectively, is undoubtedly the most promising drug of this category. We derivatized PBTZ169 into a fluorescent chemical probe that efficiently, covalently and selectively labels the enzyme DprE1, thereby localizing the target of BTZs to the periplasm at the poles of actinobacteria. We further discuss the potential applications of such probes for in vivo imaging, mycobacterial detection and designing new diagnostic tools. In general, the search for novel anti-mycobacterial drugs is an extremely long process, delaying the progression of new compounds down the pipeline and to the clinic. Assessing drug efficacy in vivo typically requires extensive resources and is time-consuming. This process can be shortened by applying alternative and innovative methods devised in this thesis, namely the implementation of in vivo imaging procedures and use of the zebrafish embryo model of mycobacterial infection for drug discovery and development. In vivo imaging enables bacterial loads in animal models to be assessed in real time, by means of fluorescence or bioluminescence imaging. We constructed, optimized and characterized genetically engineered near-infrared fluorescent reporters of the pathogens Mycobacterium marinum and M. tuberculosis that allow direct visualization of bacteria in infected zebrafish and mice, respectively. Furthermore, we show that the fluorescence level accurately reflects the bacterial load, as determined by colony forming unit enumeration, thus enabling the efficacy of antibiotic treatment to be assessed in live animals. Alternatively, we applied autobioluminescent M. tuberculosis to evaluate drug efficacy in mice and demonstrated that our system enables the therapeutic response to be followed in real time. Longitudinal imaging also reduces the number animals required thus providing a substantial gain of time and resources. Finally, the zebrafish embryo is an inexpensive and faster alternative model that has been applied to investigate mycobacterial pathogenesis. We implemented this model of M. marinum infection and successfully applied it to assess the activity of several drugs in vivo. Altogether, the innovative methods described in this work are advantageous for TB drug…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Sommer, R. C. (2019). Innovative Tools and in vivo Methods for Tuberculosis Drug Discovery and Development. (Thesis). EPFL. Retrieved from http://infoscience.epfl.ch/record/264960/files/EPFL_TH9248.pdf ; http://infoscience.epfl.ch/record/264960

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Sommer, Raphael Christopher. “Innovative Tools and in vivo Methods for Tuberculosis Drug Discovery and Development.” 2019. Thesis, EPFL. Accessed May 25, 2019. http://infoscience.epfl.ch/record/264960/files/EPFL_TH9248.pdf ; http://infoscience.epfl.ch/record/264960.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Sommer, Raphael Christopher. “Innovative Tools and in vivo Methods for Tuberculosis Drug Discovery and Development.” 2019. Web. 25 May 2019.

Vancouver:

Sommer RC. Innovative Tools and in vivo Methods for Tuberculosis Drug Discovery and Development. [Internet] [Thesis]. EPFL; 2019. [cited 2019 May 25]. Available from: http://infoscience.epfl.ch/record/264960/files/EPFL_TH9248.pdf ; http://infoscience.epfl.ch/record/264960.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Sommer RC. Innovative Tools and in vivo Methods for Tuberculosis Drug Discovery and Development. [Thesis]. EPFL; 2019. Available from: http://infoscience.epfl.ch/record/264960/files/EPFL_TH9248.pdf ; http://infoscience.epfl.ch/record/264960

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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