Research Overview
Tuberculosis (TB) is a global public health emergency and the single leading bacterial cause of death worldwide. Antibiotic treatment of TB however remains surprisingly inadequate. Current TB treatments are long and complex, often resulting in treatment failures (due to poor adherence) and multi-drug resistance. In addition, no new TB drugs have been approved in over 20 years. Fresh approaches to TB drug development are thus needed.
Nitric oxide (NO) is a natural product of the immune system that can kill Mtb as well as, or better than, most currently available TB drugs but is imperfect because of Mtb's ability to detoxify it. If we understood how NO killed Mtb by identifying its targets however, we might be able to use this information like a blueprint to design new drugs that affected these same targets and mimicked NO's ability to kill Mtb while being impervious to Mtb's NO defenses.
In previous work, we examined how NO damages Mtb. This work revealed the metabolic machinery and chemical defense systems of Mtb as major targets of NO-mediated damage. The validity of this approach was confirmed by the almost exclusive identification of target molecules essential for the growth of Mtb and the specific identification of one metabolic enzyme recently found to be definitive target of the first new potential TB drug discovered in several decades.
We are now building off this work by further evaluating the specific metabolic enzymes targeted by NO. Current TB drugs remarkably only target 4 cellular processes that largely do not involve the metabolic machinery. The results of this work could not only lead to the discovery of new TB drugs but also help present metabolic enzymes as a sensible, but previously underconsidered, class of targets for the development of much needed anti-TB drugs. From a broader perspective, this work will facilitate efforts to deduce the mechanism and targets of bio-active compounds identified in whole-organism based screening approaches.
