|Education||BS, University of Massachusetts, Amherst|
Tuberculosis is a global health concern. Tuberculosis (TB) is an infectious disease caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb). It is estimated that one third of the world is infected with Mtb, and in 2013 alone, 1.5 million people died from the disease, making Mtb the second deadliest pathogen in the world. Without treatment, two thirds of all TB cases result in death, and resistance to one or more of the frontline drugs is on the rise. The mechanisms of action of the TB frontline drug, pyrazinamide (PZA), are to date unknown but appear to target host cells without affecting the bacteria directly.
PZA inhibits PARP-1 activation. PARP-1 is a highly conserved eukaryotic nuclear enzyme that catalyzes the formation of poly-(ADP-ribose) (PAR) chains from NAD+ and regulates a wide range of cellular functions from DNA damage repair to immune activation by conjugating these negatively-charged PAR chains onto many different acceptor proteins. Because PARP-1 is inhibited by nicotinamide, a structural analog of PZA, we hypothesize that PZA acts at least in part by inhibiting PAR formation. Preliminary results from our lab suggest that PZA reduces PAR formation in a macrophage cell line treated with the PARP-1 inducer 50 µM MNNG (N-methyl-N-nitroso-N-nitroguanidine). My project aims to characterize the role of PARP-1 in TB infections and evaluate the use of potent PARP-1 inhibitors in the treatment of TB.
PARP-1 inhibitors may improve TB therapy. A better understanding of the molecular mechanisms involved in pathogenesis and disease control may lead to the development of desperately needed new drugs. Inhibition of PARP-1 may be a viable but unexplored option in TB therapy and could improve the current treatment regimen. Most importantly, this study could identify potential avenues for host-directed therapy which would be applicable to the treatment of drug-susceptible as well as drug-resistant strains of Mtb.