Taylor, Rebecca Clare (2011)
Ph.D. thesis, University of Birmingham.
Tuberculosis has been a deadly human pathogen for thousands of years and is as prevalent and lethal now as it was in the pre-antimicrobials era. With new challenges continually being presented in the form of multidrug resistant strains evolving and the implications of the HIV epidemic, it is imperative that every effort is made to understand the causative agent, Mycobacterium tuberculosis, and develop new effective and affordable drugs to treat the disease.
With this in mind, the first part of this project tests novel drugs that have been identified using different approaches. The desired targets for all the compounds were the fatty acid and mycolic acid biosynthesis systems in M. tuberculosis, Mycobacterium bovis BCG and Mycobacterium
smegmatis. Some promising compounds were identified, which inhibited enzymes of the prokaryotic FAS-II system, whilst not affecting the mammalian FAS-I system.
As well as identifying new drugs, it is equally important to recognise the essential genes of M. tuberculosis, which could be novel drug targets. Whilst the fatty acid biosynthesis pathway has been well studied, a lot less is known about fatty acid degradation. M. tuberculosis has an
abundance of fad genes, yet it is only recently that they have started to be explored. Here, the functions and roles of the fadB genes in M. tuberculosis, M. bovis BCG and M. smegmatis have been explored. By producing purified recombinant protein and generating gene deletion mutants, it has been possible to fully characterise Mt-FadB2 and provide preliminary information regarding fadB3, fadB4 and fadB5.
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