The TB Alliance is exploring a group of drug targets that is unknown in the world of TB drugs but well known to others. In the fight against HIV/AIDS, the so-called protease inhibitors have become powerful components of current antiretroviral therapies. But the potential of inhibitors against the same family of enzymes from Mycobacterium tuberculosis (M.tb), the causative agent of TB, remains unexplored. If inhibitors of M.tb proteases can be discovered, their novelty would make them potentially powerful drugs against multidrug-resistant and extremely drug-resistant TB (MDR-TB and XDR-TB).
In partnership with Prof. Tanya Parish at the Infectious Disease Research Institute (IDRI), a Seattle-based non-profit scientific research institute, the TB Alliance will work out which of the many proteases in M.tb might make the best targets for TB drugs. The first priority will be proteases that are essential for M.tb's survival in animals. Parish has a promising start on this part of the project, as several proteases seem to be important for M.tb to stay alive in low oxygen or low nutrient conditions. Survival in these circumstances is thought to be critical for the persistence of M.tb in humans, so drugs that prevent this survival have a good chance of shortening TB treatments.
The collaboration will then focus on generating M.tb strains that produce more or less than normal of a particular protease. Potential drugs that shut down a particular protease would be expected to struggle in M.tb strains that have a lot of that target protease, but do especially well in M.tb strains that have little of the protease. This approach allows the team to focus on a single target, but to do so in the context of whole cells. Drug candidates that work in whole cells are more likely to advance, as they have already passed the test of penetrating and working within cells.