6bpy
Aspergillus fumigatus Thioredoxin ReductaseAspergillus fumigatus Thioredoxin Reductase
Structural highlights
FunctionPublication Abstract from PubMedAspergillus fumigatus infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent need for new antifungals. Thioredoxin reductase (TrxR) is essential for maintaining redox homeostasis and presents as a promising target for novel antifungals. We show that ebselen [2-phenyl-1,2-benzoselenazol-3(2H)-one] is an inhibitor of A. fumigatus TrxR (Ki = 0.22 muM) and inhibits growth of Aspergillus spp., with in vitro MIC values of 16 to 64 microg/ml. Mass spectrometry analysis demonstrates that ebselen interacts covalently with a catalytic cysteine of TrxR, Cys148. We also present the X-ray crystal structure of A. fumigatus TrxR and use in silico modeling of the enzyme-inhibitor complex to outline key molecular interactions. This provides a scaffold for future design of potent and selective antifungal drugs that target TrxR, improving the potency of ebselen toward inhbition of A. fumigatus growth. Structure, Mechanism, and Inhibition of Aspergillus fumigatus Thioredoxin Reductase.,Marshall AC, Kidd SE, Lamont-Friedrich SJ, Arentz G, Hoffmann P, Coad BR, Bruning JB Antimicrob Agents Chemother. 2019 Feb 26;63(3). pii: AAC.02281-18. doi:, 10.1128/AAC.02281-18. Print 2019 Mar. PMID:30642940[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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