Identifying the mode of action of novel anti-tubercular drugs

Cox, Jonathan A. G. (2015). Identifying the mode of action of novel anti-tubercular drugs. University of Birmingham. Ph.D.

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The demand for novel antibiotics in the treatment of infections by \(Mycobacterium\) \(tuberculosis\) (\(M.\) \(tb\)), the causative agent of tuberculosis (TB) has reached new highs with the recent emergence of totally-drug resistant TB (TDR-TB). Efforts to develop antibiotics with revolutionary mechanisms of action, low minimal inhibitory concentrations (MICs) that will decrease the current drug burden and clear infection without compromising side effects has led to several collaborative efforts between pharmaceutical companies and academic institutions throughout the world. This interdisciplinary collaborative effort and advances in drug development technologies, such as high throughput phenotypic screening of compound libraries and whole genome sequencing (WGS) has accelerated the identification of new compounds (or hits) with potent anti-tubercular activity and delivered a variety of unique drug targets. These hits are also potent against drug-resistant strains of \(M.\) \(tb\), and have significant efficacy \(in\) \(vivo\) models of TB infection. Bedaquiline (Sirturo™) is the first new specifically designed anti-TB drug to be approved by the Food and Drug Administration (FDA) for use against multi-drug resistant (MDR-TB) in 40 years. This considerable step forward marks the beginning of a paradigm shift in antibiotic development, signaling a new age of drug discovery. In this thesis, the modern age of TB drug discovery will be examined as well as the efforts made to further this field through the identification of novel hits with activity against \(M.\) \(tb\) and identifying their respective inhibitory mechanisms.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Life & Environmental Sciences
School or Department: School of Biosciences
Funders: Biotechnology and Biological Sciences Research Council
Subjects: Q Science > QR Microbiology


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