Research Team Discovers TB Disease Mechanism and Molecule to Block It

Indiana University School of Medicine researchers have identified a mechanism used by the tuberculosis bacterium to evade the body's immune system and have identified a compound that blocks the bacterium's ability to survive in the host, which could lead to new drugs to treat tuberculosis.

Zhong-Yin Zhang, PhD, the Robert A. Harris Professor and chairman of the Department of Biochemistry and Molecular Biology, and his colleagues revealed the biochemical processes that TB bacteria employ to subvert macrophages – key infection-fighting cells – in this week's online early edition of the Proceedings of the National Academy of Sciences. They also described a compound they have synthesized – I-A09 – that blocked the TB bacterium's activity in laboratory tests.

About one-third of the world's population is infected with TB, a contagious disease that causes nearly 2 million deaths annually, according to the Centers for Disease Control and Prevention (CDC). 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. People 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.

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, Zhang said. If it can be developed into an approved drug, the result could significantly shorten treatment times for TB, he said.

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

The research was supported by grants from the National Institutes of Health.