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Publication Abstract from PubMed

Candida auris has emerged as a global health problem with a dramatic spread by nosocomial transmission and a high mortality rate. Antifungal therapy for C. auris infections is currently limited due to widespread resistance to fluconazole and amphotericin B and increasing resistance to the front-line drug echinocandin. Therefore, new treatments are urgently required to combat this pathogen. Dihydrofolate reductase (DHFR) has been validated as a potential drug target for Candida species, although no structure of the C. auris enzyme (CauDHFR) has been reported. Here, crystal structures of CauDHFR are reported as an apoenzyme, as a holoenzyme and in two ternary complexes with pyrimethamine and cycloguanil, which are common antifolates, at near-atomic resolution. Preliminary biochemical and biophysical assays and antifungal susceptibility testing with a variety of classical antifolates were also performed, highlighting the enzyme-inhibition rates and the inhibition of yeast growth. These structural and functional data might provide the basis for a novel drug-discovery campaign against this global threat.

Crystal structure of dihydrofolate reductase from the emerging pathogenic fungus Candida auris.,Kirkman T, Sketcher A, de Morais Barroso V, Ishida K, Tosin M, Dias MVB Acta Crystallogr D Struct Biol. 2023 Aug 1;79(Pt 8):735-745. doi: , 10.1107/S2059798323004709. Epub 2023 Jul 10. PMID:37428844^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.