Date of Completion

8-22-2018

Embargo Period

8-21-2018

Keywords

Folate biosynthetic pathway, Tuberculosis, Mycobcateria, Propargyl-linked antifolates, Dihydrofolate reductase, Infectious diseases, antimicrobial resistance

Major Advisor

Dr. Dennis Wright

Associate Advisor

Dr. Victoria Robinson

Associate Advisor

Dr. Kyle Hadden

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has co-evolved with humans since the dawn of our species. Despite advances in antibiotic therapy, TB global burden is till enormous. Antimicrobial resistance and HIV epidemic challenge the ongoing efforts to control TB. Novel anti-TB agents are required to address the issues associated with current drug regimens and to improve the outcomes of TB therapy. In this work, we have evaluated the antimycobacterial activity of propargyl-linked antifolates against drug-susceptible and drug-resistant M. tuberculosis. Antifolates exerts their antimicrobial effect by interruption of folate biosynthetic pathway and one-carbon metabolism. We have successfully identified a few novel antifolates with potent antimycobacterial activity. Through comparison of these compounds with para-aminosalicylic acid, a second-line anti-TB agent, we were able to elucidate the mechanism of action of both. Finally, we have shown that these compounds are also potent inhibitors of M. avium complex, another group of pathogenic Mycobacteria. We suggest that propargyl-linked antifolates are excellent candidate for future drug development as antimycobacterial agents.

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