Research Profiles

ANTI-TB DRUG PROGRAMME

Professor Bill Denny and Associate Professor Brian Palmer and their team are developing new drugs to treat tuberculosis (TB) more effectively. Tuberculosis is re-emerging as a world health emergency, due in part to its co-occurrence with HIV infection, and the development of treatment-resistant strains of the bacterium. It is estimated that one third of the world’s population is infected with the latent form of TB; of these, each year 9 million people will develop the active, contagious form of the disease, and of these 2-3 million will die from their infection. The current treatment for TB requires that a cocktail of antibiotic drugs be taken continuously for at least six months. There is an urgent need for more active, shorter regimen treatments for TB, particularly against the dormant and drug-resistant forms. The New York-based Global Alliance for TB drug development (GATB) is currently sponsoring a clinical trial of the first radically different anti-TB drug to be developed in 40 years, known as PA-824. PA-824 is particularly active against the dormant stages of TB and it began phase 1 trials in human volunteers in mid-2005.

Prof. Denny and A-P Palmer have been awarded generous funding from the GATB to develop second-generation analogs of PA-824, seeking to establish more potent activity and an improved pharmacokinetic profile. The Auckland chemistry team, based at the Auckland Cancer Society Research Centre, comprises five medicinal chemists who have to date prepared more than 200 compounds for evaluation against cultures of the TB bacterium. Several highly active compounds have now been identified, the most potent of which have been prepared in sufficient quantities to enable their on-going evaluation in a mouse model of TB. The activity of PA-824 and its analogs is believed to result from their metabolic activation within the bacterium. In collaboration with Prof. Ted Baker’s group at the SBS, investigations of several key enzymes of the TB bacterium are underway, including those that metabolize PA-824, to better understand the target of this new class of prodrugs