Institute for Photonics and Advanced Sensing, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
National Mycology Reference Centre, SA Pathology, Adelaide, South Australia, Australia.
Antimicrob Agents Chemother. 2019 Feb 26;63(3). doi: 10.1128/AAC.02281-18. Print 2019 Mar.
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 TrxR ( = 0.22 μM) and inhibits growth of spp., with 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 TrxR and use 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 growth.
感染与高死亡率和高治疗成本相关。有限的可用抗真菌药物和不断增加的抗真菌耐药性突出表明迫切需要新的抗真菌药物。硫氧还蛋白还原酶 (TrxR) 对于维持氧化还原稳态至关重要，是新型抗真菌药物的有希望的靶标。我们表明，依布硒啉 [2-苯基-1,2-苯并硒唑-3(2H)-酮] 是 TrxR 的抑制剂（=0.22μM），并抑制生长，MIC 值为 16 至 64μg/ml。质谱分析表明，依布硒啉与 TrxR 的催化半胱氨酸 Cys148 发生共价相互作用。我们还呈现了 TrxR 的 X 射线晶体结构，并使用酶-抑制剂复合物的建模来概述关键的分子相互作用。这为未来设计针对 TrxR 的有效且选择性的抗真菌药物提供了一个支架，提高了依布硒啉抑制生长的效力。
