These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Identification of P218 as a Potent Inhibitor of Mycobacteria Ulcerans DHFR
preprintsubmitted on 31.08.2020, 19:51 and posted on 01.09.2020, 12:56 by Gustavo Pelicioli Riboldi, Rachael Zigweid, Peter J. Myler, Stephen J. Mayclin, Rafael Counago, Bart L. Staker
Mycobacterium ulcerans 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 de novo biosynthesis of folate species and is a validated target for several antimicrobials. Here we describe the biochemical and structural characterization of M. ulcerans 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 M. ulcerans DHFR as a target for future structure-based drug discovery campaigns.