Aspergillus fumigatus thioredoxin reductase: structure, mechanism, and inhibition.

Aspergillus fumigatus thioredoxin reductase: structure, mechanism, and inhibition. Antimicrob Agents Chemother. 2019 Jan 14;: Authors: Marshall AC, Kidd SE, Lamont-Friedrich SJ, Arentz G, Hoffmann P, Coad BR, Bruning JB Abstract Aspergillus 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 μM) and inhibits growth of Aspergillus spp. with in vitro MIC values of 16-64 μg/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 upon the potency of ebselen towards inhbition of A. fumigatus growth. PMID: 30642940 [PubMed - as supplied by publisher]
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research