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2020-08-31-RXiv-MulDFR.pdf (1.08 MB)
Identification of P218 as a Potent Inhibitor of Mycobacteria Ulcerans DHFR
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
submitted on 31.08.2020 and posted on 01.09.2020by Gustavo Pelicioli Riboldi, Rachael Zigweid, Peter J. Myler, Stephen J. Mayclin, Rafael Counago, Bart L. Staker
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