Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of bloodstream infections in hospitals throughout the world. Compounding this issue is the rapid emergence of community-acquired MRSA infections in healthy individuals and difficulty within the pharmaceutical industry regarding the discovery of novel and effective antibiotics to treat bacterial pathogens that are resistant to traditional antibiotics. The de novo folate pathway in bacteria, a pathway that is absent in humans, leads to necessary precursors for cellular function and is a current target of antimicrobials, including the sulfonamides which target the enzyme dihydropteroate synthase (DHPS). The folate pathway involves a number of other enzymes that have not yet been exploited as drug targets including the precursor to DHPS, 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme that catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin.

Using x-ray crystallography, we have solved ternary complexes of novel inhibitors with cofactor-bound Staphylococcus aureus HPPK, in addition to a structure of the cofactor-bound binary complex. These structures, in addition to NMR experimental data, have revealed insight into the binding of these compounds and have aided in us developing a series of analogues with improved affinity and ligand-efficiency with the potential to be further developed into efficacious antibacterials.