Open AccessIdentification of P218 as a potent inhibitor of Mycobacterium ulcerans DHFR
Author(s) -
Gustavo Pelicioli Riboldi,
Rachael Zigweid,
Peter J. Myler,
Stephen J. Mayclin,
R.M. Counago,
Bart L. Staker
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d0md00303d
Subject(s) - mycobacterium ulcerans , virology , biology , buruli ulcer , microbiology and biotechnology , medicine , pathology , disease
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.