Identification of P218 as a potent inhibitor of Mycobacterium ulcerans 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 o...

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Bibliographic Details
Published in:MedChemComm 2021-01, Vol.12 (1), p.103-109
Main Authors: Riboldi, Gustavo P, Zigweid, Rachael, Myler, Peter J, Mayclin, Stephen J, Couñago, Rafael M, Staker, Bart L
Format: Article
Language:English
Subjects:
Antibiotics
Antimicrobial agents
Biosynthesis
Buruli ulcer
Chemistry
Chronic illnesses
Dihydrofolate reductase
Enzymes
Folic acid
Inhibitors
Malaria
Medical treatment
Mycobacterium ulcerans
Reductases
Side effects
Structural analysis
Ulcers
Vector-borne diseases
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Summary: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.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d0md00303d