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2020-08-31-RXiv-MulDFR.pdf (1.08 MB)
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Identification of P218 as a Potent Inhibitor of Mycobacteria Ulcerans DHFR

preprint
submitted on 31.08.2020 and posted on 01.09.2020 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.

Funding

FAPESP 2013/50724-5

FAPESP 2014/50897-0

CNPq 465651/2014-3

Wellcome 106169/ZZ14/Z

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201700059C

History

Email Address of Submitting Author

rafael.counago@unicamp.br

Institution

Universidade Estadual de Campinas (UNICAMP)

Country

Brazil

ORCID For Submitting Author

0000-0003-1847-5090

Declaration of Conflict of Interest

no conflict of interest

Version Notes

2020-08-31-version1

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