Global Health
I am based in New York in the Division of International Medicine and Infectious Diseases. We are working on identifying new potential Tuberculosis (TB) drug targets. Nitric oxide (NO) is a natural product of the immune system that, in a test tube, can kill Mtb as well as, or better than, most antibiotics currently used to treat TB. In humans however, this killing is incomplete and may, in part, be explained by Mtb’s ability to detoxify NO. Based on this knowledge, we believe that the antimycobacterial activity of NO against Mtb can be used as a blueprint to new potential TB drug targets. That is, if we could identify critical targets of NO-mediated damage in Mtb, we might be able to design drugs to inhibit these same targets, mimic NO's antimicrobial effects, and resist Mtb’s NO defenses. Chemical inhibitors of these same targets should be no less effective than NO, more effective than NO by avoiding Mtb’s NO-detoxifying machinery and effective in immuno-suppressed individuals who produce inadequate amounts of NO. Using proteomically-based techniques, we have identified 31 such potential targets. All are enzymes that mostly serve intermediary metabolism and/or anti-oxidant defense. Surprisingly, many of these proteins overlap with factors or processes known to be important for the pathogenesis of tuberculosis. One such protein was recently identified as the definitive target of the first new potential TB drug discovered in several decades. We are now pursuing these studies with the use of novel mass spectrometry-based tools that enable comprehensive metabolite profiling of Mtb. Overall, it is hoped that the results of this work will lead to the identification of new TB drug targets and the validation of Mtb metabolic enzymes as a sensible, but previously underconsidered, class of potential drug targets.
I would be delighted to have any interested students.
