2023 71 B3

Investigating Inhibitors of Flavin-Dependent Thymidylate Synthase (FDTS) from Mycobacterium tuberculosis (M. Tb)

By: Su Ozcan, Nisa Mostarshed

Department: Chemistry & Biochemistry

Faculty Advisor: Dr. Eric Koehn

Tuberculosis (TB) is a major global health concern caused by Mycobacterium tuberculosis (M.tb), which infects the lungs and can be transmitted through the air. According to the World Health Organization, TB is responsible for over 10 million infections and 1.5-2 million deaths annually. Current treatments are becoming less effective since M.tb mutates rapidly and develops drug resistance. As a result, TB requires more effective treatments, and one enticing avenue for new third-line antibiotic drugs is to target DNA biosynthesis within TB selectively over human DNA biosynthesis. One potential target to interrupt DNA biosynthesis is targeting the thymidylate synthase, which catalyzes the formation of the essential base, deoxythymidine monophosphate (dTMP). In humans, dTMP is produced by classical Thymidylate Synthase (TSase) enzymes, whereas specific pathogens such as M.tb rely on an alternative enzyme called Flavin Dependent Thymidylate Synthase (FDTS). In this work, the KOEHN Laboratory investigates inhibitors of MtbFDTS by kinetic and thermodynamic biochemical assays and through structural characterization. As the KOEHN Laboratory, we are also developing novel phosphorylation methods of nucleoside analogs to produce potential nucleotide analog inhibitors. Since very few nucleoside/tides antibiotics are effective against any bacteria, our approach could revolutionize drug development by targeting novel pathways involved in DNA biosynthesis within M.tb.