Unknown

Dataset Information

0

Structure, Mechanism, and Inhibition of Aspergillus fumigatus Thioredoxin Reductase.


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??M) and inhibits growth of Aspergillus spp., with in vitro MIC values of 16 to 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 the potency of ebselen toward inhbition of A. fumigatus growth.

SUBMITTER: Marshall AC 

PROVIDER: S-EPMC6395915 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

Structure, Mechanism, and Inhibition of <i>Aspergillus fumigatus</i> Thioredoxin Reductase.

Marshall Andrew C AC   Kidd Sarah E SE   Lamont-Friedrich Stephanie J SJ   Arentz Georgia G   Hoffmann Peter P   Coad Bryan R BR   Bruning John B JB  

Antimicrobial agents and chemotherapy 20190226 3


<i>Aspergillus fumigatus</i> 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 <i>A. fumigatus</i> TrxR (<i>K<sub>i</sub></i> = 0.22 μM) and inhi  ...[more]

Similar Datasets

| S-EPMC3398318 | biostudies-literature
| S-EPMC2733882 | biostudies-literature
| S-EPMC7583042 | biostudies-literature
| S-EPMC3508724 | biostudies-literature
| S-EPMC4881748 | biostudies-literature
| S-EPMC7293542 | biostudies-literature
| S-EPMC6154143 | biostudies-literature
| S-EPMC55487 | biostudies-literature
2024-12-23 | GSE282324 | GEO
2024-12-23 | GSE282325 | GEO