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B.S., University of Wisconsin, LaCrosse, WI, 2010
M.S., Boston University ,Boston, MA, 2013
Honors and awards:
Mycobacterium tuberculosis, the causative agent of tuberculosis, is responsible for an estimated 1.5 million deaths annually. Although an effective treatment regimen exists, its implementation is challenging because it involves a minimum of six months of therapy with drugs that are associated with adverse reactions. These factors contribute to complications that have been implicated in the emergence of drug-resistant strains of M. tuberculosis. para-Aminosalicylic acid (PAS), is used to treat drug-resistant M. tuberculosis infections. PAS is thought to disrupt folate metabolism by inhibition of dihydrofolate reductase (DfrA), although the precise
mechanism for inhibition is still unresolved. We have shown that PAS is bioactivated to hydroxyl-dihydrofolate and which we found inhibits DfrA via a slow tight binding mechanism. The ability of PAS to disrupt folate metabolism is supported by the identification of molecular resistance mechanisms associated with mutation of genes involved in folate metabolism, namely folC (encoding dihydrofolate synthase) and thyA (encoding a non-essential thymidylate synthase). The biochemical mechanism(s) that govern PAS resistance associated with these mutations is still unknown. We have shown that genes involved in para-aminobenzoic acid (PABA) synthesis are up-regulated in folC resistant mutants suggesting that increased PABA biosynthesis maybe the biochemical basis for FolC linked resistance. Elucidating the mechanisms that govern the biochemical susceptibility and resistance of M. tuberculosis to existing anti-tubercular agents will facilitate the discovery of new therapeutic approaches to shorten treatment times and counter drug-resistance.