Scientists find TB disease mechanism along with compound to block it

Scientists at Indiana University School of Medicine have discovered a TB disease mechanism along with a compound to block it.

The tuberculosis bacterium evades the body's immune system using this mechanism but the finding of a molecule that blocks the bacterium's ability to survive in the host could lead to development of new drugs to treat the disease.

Zhong-Yin Zhang, Ph.D., Robert A. Harris Professor and chairman of the Department of Biochemistry and Molecular Biology, and his colleagues found the biochemical processes that TB bacteria employ to subvert macrophages - key infection-fighting cells.

They have also described a compound they have synthesized - I-A09 - that blocked the TB bacterium's activity in laboratory tests.

Although medicines to treat TB are available, they must be taken for at least six months to fully eliminate all TB bacteria from the body. Patients  who do not follow the lengthy treatment regimen can become sick and infectious with a more virulent form of the disease that is resistant to standard medicines.

According to Zhang, the compound synthesized by the IU group is a proof of concept that a small molecule drug targeted against an essential virulent factor of the TB bacterium can be an effective strategy. He said if it can be developed into an approved drug, the result could significantly shorten treatment times for TB.

The focus of the research was TB actions inside macrophages, which are infection fighting cells in the body's immune system. Macrophage cells' tools include the production of special proteins called cytokines to attack foreign invaders. Infected macrophages can also kick off a self-destruction mechanism called apoptosis, which signals other immune system cells to mount a defense against the infection.

TB bacteria are able to disable the macrophage defenses by secreting virulent factors into the host. The IU team found that the actions of a particular virulent factor - a protein phosphatase enzyme called mPTPB - blocked both the production of the infection-fighting cytokines, and the macrophage's self-destruct system.

Using combinatorial chemical synthesis and high-throughput screening, the researchers developed the I-A09 compound, which successfully blocked the action of mPTPB. Tests involving live TB bacteria were conducted at the Institute of Tuberculosis Research, University of Illinois at Chicago.

Currently, compound I-A09 is being evaluated in a TB animal model at the Johns Hopkins University School of Public Health.

Zhang said more potent forms of the I-A09 compound are being pursued by the IU team for possible future clinical testing.

The findings of the study have appeared in this week's online early edition of the Proceedings of the National Academy of Sciences.