Structure, mechanism, and inhibition of Aspergillus fumigatus thioredoxin reductase

Andrew C Marshall, Sarah E Kidd, Stephanie J Lamont-Friedrich, Georgia Arentz, Peter Hoffmann, Bryan R Coad, John B Bruning

Research output: Contribution to journalArticle

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.

LanguageEnglish
Article numbere02281-18
Number of pages15
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number3
Early online date14 Jan 2019
DOIs
Publication statusE-pub ahead of print - 14 Jan 2019
Externally publishedYes

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Thioredoxin-Disulfide Reductase
Aspergillus fumigatus
Enzyme Inhibitors
Aspergillus
Growth
Health Care Costs
Computer Simulation
Oxidation-Reduction
Cysteine
Mass Spectrometry
Homeostasis
X-Rays
Mortality
Infection
Pharmaceutical Preparations
ebselen

Cite this

Marshall, A. C., Kidd, S. E., Lamont-Friedrich, S. J., Arentz, G., Hoffmann, P., Coad, B. R., & Bruning, J. B. (2019). Structure, mechanism, and inhibition of Aspergillus fumigatus thioredoxin reductase. Antimicrobial Agents and Chemotherapy, 63(3), [e02281-18]. https://doi.org/10.1128/AAC.02281-18
Marshall, Andrew C ; Kidd, Sarah E ; Lamont-Friedrich, Stephanie J ; Arentz, Georgia ; Hoffmann, Peter ; Coad, Bryan R ; Bruning, John B. / Structure, mechanism, and inhibition of Aspergillus fumigatus thioredoxin reductase. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 3.
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Marshall, AC, Kidd, SE, Lamont-Friedrich, SJ, Arentz, G, Hoffmann, P, Coad, BR & Bruning, JB 2019, 'Structure, mechanism, and inhibition of Aspergillus fumigatus thioredoxin reductase' Antimicrobial Agents and Chemotherapy, vol. 63, no. 3, e02281-18. https://doi.org/10.1128/AAC.02281-18

Structure, mechanism, and inhibition of Aspergillus fumigatus thioredoxin reductase. / Marshall, Andrew C; Kidd, Sarah E; Lamont-Friedrich, Stephanie J; Arentz, Georgia; Hoffmann, Peter; Coad, Bryan R; Bruning, John B.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 3, e02281-18, 03.2019.

Research output: Contribution to journalArticle

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AU - Marshall, Andrew C

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AU - Coad, Bryan R

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AB - 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.

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