Structural Investigation of Essential Enzymes in Pathogenic Bacteria and Evaluation of Drug Candidates

The cell wall is a common component found in nearly all bacteria. Long validated as a drug target for over half of all prescribed antibiotics, it continues to offer new sources for increasing that number ever further. Eschewing the ubiquitous transpeptidase-targeting beta lactams, pathways for the biosynthesis of the rhamnose linker between peptidoglycan and arabinogalactan, and peptidoglycan itself, provide alternatives for developing novel antibiotics to pathogenic bacteria. The first half of this study will focus on the fourmember pathway responsible for the production of dTDP-Lrhamnose and includes a structural analysis of some members found in Mycobacterium tuberculosis (Mtb) in conjunction with their respective inhibitors. The specific architecture of each individual inhibitor inside the active site of the enzyme offers insight into the role each atom plays in binding and explains why small variations of the compound influence this relationship. This same variation also affects the ability of the compound to reach its target inside the cell. The second half of this study will focus on the first step of the pathway for biosynthesis of uridine diphosphate N-acetylmuramic acid pentapeptide, the immediate precursor to peptidoglycan. UDP-Nacetylglucosamine enolpyruvyl transferase (MurA) catalyzes the transfer of the enolpyruvyl moiety of phosphoenolpyruvate to the 3’ hydroxyl group of UDP-Nacetylglucosamine, yielding enolpyruvyl-UDP-Nacetylglucosamine and phosphate. This enzyme is highly conserved among bacteria and found as a single copy in gram negative bacteria