Exploitable results Mechanistic basis of isoniazid activation in tuberculosis treatment: A molecular model for developing lead compounds to combat drug resistance In 1993 the World Health Organization declared tuberculosis (TB) to be a global emergency. Concern over the spread of the disease has been heightened by the increasing number of TB-causing bacilli which are resistant to at least one of the frontline drugs used to treat the disease including the core compound isoniazid. With support from the Biomed 2 programme funded under Framework IV, our work has focussed upon developing and understanding the function of an enzyme, catalase-peroxidase (CP). This enzyme is present in Mycobacterium tuberculosis (the principal causative agent of TB), and is proposed to be responsible for necessary activation of isoniazid which is required for treatment of the disease. The success of our studies has relied upon an interplay between groups specialising in different disciplines from protein chemistry (Imperial College, London, UK), to synthetic organic chemistry (University of Nancy, FR) and inorganic chemistry/nuclear magnetic resonance (NMR) spectroscopy (University of Florence, IT). Significant results include the establishment of a system for the high-level production and efficient purification of recombinant CP. The availability of this material has enabled a range of enzymological and spectroscopic studies to be undertaken which has yielded fundamental details about the activities of CP which may be responsible for activation of isoniazid. In addition, complementary work has led to efficient and novel synthetic rotes for producing 15N-labelled derivatives of isoniazid from commercially available 15N-potassium phthalimide (Figure 1). These compounds are proving of great value in understanding the exact chemical processes involved in drug processing and have also led to the production of a 1,1-bis protected hydrazine which can be used in a large range of other synthetic applications. We have also recently defined the first three-dimensional model for the binding of isoniazid in a related enzyme-system horseradish peroxidase (Figure 2) using NMR methods. This model can provide a useful starting point for further studies designed to test hypotheses regarding isoniazid activation in vitro and possibly in vivo. Searching for OpenAIRE data... There was an error trying to search data from OpenAIRE No results available
