Identification of P218 as a potent inhibitor of DHFR.

is the causative agent of Buruli ulcer, a debilitating chronic disease that mainly affects the skin. Current treatments for Buruli ulcer are efficacious, but rely on the use of antibiotics with severe side effects. The enzyme dihydrofolate reductase (DHFR) plays a critical role in the biosynthesis of folate species and is a validated target for several antimicrobials. Here we describe the biochemical and structural characterization of DHFR and identified P218, a safe antifolate compound in clinical evaluation for malaria, as a potent inhibitor of this enzyme. We expect our results to advance DHFR as a target for future structure-based drug discovery campaigns.