We all know how TB has become a pandemic and several attempts to eradicate the disease have been tried and scientists are still finding new ways. However the most disadvantage part for the scientists lies in the fact that "the disease-causing bacteria have a sophisticated mechanism for surviving dormant in infected cells". i.e., TB bacteria have a sophisticated way to remove the damaged proteins — a protein-cleaving complex known as a proteasome — identified in earlier research by the Nathan lab. By breaking down damaged proteins, the proteasome allows the bacteria to remain dormant, and possibly go on to cause active TB. And hence finding drugs to disable the proteasome would be a new way to fight TB.
In developing proteasome-inhibitor drugs, scientists face several hurdles. A significant one is the fact that human cells also possess proteasomes, which are essential to their survival. To be effective, the drugs would have to specifically target the TB proteasome without adversely affecting the human protein-cleanup complex.
This study represents a shift in strategy for designing antibiotics that treat TB, says Dr. Lin (Assistant Research professor of Microbiology and Immunology at Weill Cornell Medical College). All the groups who tried focused on developing drugs that attacked the bacterium in its active phase, but this group has found a compound that may help to destroy it in its dormant stage.
The Weill Cornell team screened 20,000 compounds for TB proteasome inhibition activity. They identified and synthesized a group of inhibitors, which they then tested for their ability to inhibit the proteasome inside the mycobacteria. They also tested the compounds' effect on monkey epithelial cells and human immune system cells in culture. After reading this article, I could recollect the High Throughput Screening of my compounds (Southern Research Institute, Birmingham). The newly synthesized compounds are specific, less toxic, more active and more over the inhibition of the TB proteasome is irreversible and about 1,000-fold more effective than the minor inhibition observed against human proteasomes.
The Weill Cornell team screened 20,000 compounds for TB proteasome inhibition activity. They identified and synthesized a group of inhibitors, which they then tested for their ability to inhibit the proteasome inside the mycobacteria. They also tested the compounds' effect on monkey epithelial cells and human immune system cells in culture. After reading this article, I could recollect the High Throughput Screening of my compounds (Southern Research Institute, Birmingham). The newly synthesized compounds are specific, less toxic, more active and more over the inhibition of the TB proteasome is irreversible and about 1,000-fold more effective than the minor inhibition observed against human proteasomes.
The structural studies revealed that the inhibitor molecules block the proteasome's ability to degrade proteins in more than one way: by producing a direct chemical change to the proteasome active site, and by altering the conformation of the "pocket" into which protein fragments bind before being degraded. Congrats for this efforts and all the best for their future endeavor.... More....
