Many essential enzymes are highly conserved between species, yet exhibit subtle structural differences that can account for widely disparate affinities toward the same small molecule. Thymidylate synthase (TS), a target of several cancer drugs in humans, is one such enzyme, with extraordinary conservation of sequence and structure across many species, including tuberculosis, malaria, and other pathogenic organisms. My research is concerned with designing selective inhibitors for thymidylate synthases (TS) found in virulent strains of Escherichia coli via a fragment-based approach. This method allows us to find small molecules that bind in different portions of the active site which can subsequently be linked together to yield a lead compound. Using ligand-based NMR screening techniques, crystallographic methods, and biochemical activity assays in conjunction permits a rational and efficient method of drug discovery.