The biosynthesis of Mycobactin T, a virulence factor from Mycobacterium tuberculosis.

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Mycobacterium tuberculosis is the causative agent of tuberculosis. The drug isoniazid led to a dramatic and sustained decline in mortality due to tuberculosis. This led to it being described in medical literature in 1988 as a disappearing disease which was now fairly easy to treat. However, the advent of HIV and the rapid rise of multidrug resistant M. tuberculosis led to dramatic changes. The risk that an HIV infected individual will develop active tuberculosis is 7% per year, compared to a lifetime risk of 10% for an immunocompetent person. Similarly, the prevalence of drug resistant strains of M. tuberculosis is over 5% in many regions, including SE asia. Mycobacterial infections are regarded as the leading cause of morbidity and mortality world wide and WHO estimates that 30 million deaths will occur in the next decade due to these infections. Clearly, new drugs are required to combat the rising menace of this organism. The aim of this project is to detail the unique metabolic pathways in M. tuberculosis that produce Mycobactin T, essential to the virulence of this organism. Mycobactin T helps the bacteria obtain iron, an essential nutrient. These factors make the mycobaction pathway an ideal drug target and an understanding of its biochemistry is essential to its eventual exploitation for intervention in M. tuberculosis infections. We hypothesise that it may already provide the unknown site of action of a clinically employed, antituberculosis drug para-aminosalicylate (PAS). This project will i) fully define the structure of mycobactin T; ii) clone and overexpress key genes which catalyse the first three steps of mycobactin formation; iii) purify and characterise the overexpressed proteins with respect to their biochemical function; iv) examine the interaction of PAS with the proteins likely to be targeted by this antimycobacterial agent. The results of this work will provide the basis for the development of future anti-tuberculosis drugs.