Studies suggest new targets for TB treatments
tuberculosis (TB) treatments, which could essentially dictate the
design of TB drugs of the future. The bacterium that causes TB
currently infects one person in three worldwide.
Established drugs for tuberculosis suffer from high compliance as well as mechanisms of action that are becoming increasingly outdated and ineffective. Coupled with the worldwide rise of multi-drug resistance TB strains and the global spread of HIV, its spread has been exacerbated by a variety of reasons, one of which includes the large numbers of people from all over the world who travel.
The study revealed that TB bacteria removed the protein-cleaving complexes known as proteasomes. This protein cleanup mechanism allows Mycobacterium tuberculosis to remain in macrophages, and possibly go on to cause active TB infections. With details revealed, it could also serve as a target for new anti-TB drugs.
"If we could find a way to specifically inhibit the activity of this Mycobacterium tuberculosis proteasome, then we might have a new, effective treatment for TB," said biophysicist Huilin Li, who led the research.
"Such a treatment might even eradicate TB microbes from infected individuals who show no signs of infection."
However, one complicating factor is that human cells also contain proteasomes for degrading unneeded proteins. This process is essential for human cell survival. So any drug targeting the TB proteasome would have to be extremely specific.
This was the prime reason for conducting such detailed structural and biochemical studies, to try to identify the unique characteristics that would allow such a targeted drug design.
In addition, the scientists conducted studies to see how an analog for an anti-myeloma drug that targets human proteasomes binded to the TB proteasome.
These studies revealed details of the proteasome active site and mechanism, which could prove invaluable to designing TB specific inhibitors.
"Understanding the structure and biochemistry of this proteasome, and how it is different from those found in human cells, could greatly improve prospects for developing specific proteasome-based anti-tuberculosis treatments," said biophysicist Huilin Li, who led Brookhaven's role in the research.
The Global Alliance for TB development estimates the TB market size will grow from around $440 million (€354 million) in 2000, to almost $700 million by 2010, and although this represents a comparatively small market size, careful product placement and market strategies could drive a more significant growth in the market.
The research is published in two papers in the March 2006 issue of Molecular Microbiology.
