Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis
Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis
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DOI：
10.1073/pnas.1504022112
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发表时间：
2015-04-07
影响因子：
11.1
通讯作者：
Wang, Feng
中科院分区：
文献类型：
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作者：
Harbut, Michael B.;Vilcheze, Catherine;Wang, Feng
由抗生素耐药细菌引起的感染是一个日益严重的公共卫生威胁，这使得新抗生素的鉴定成为当务之急。通过在营养剥夺条件下针对结核分枝杆菌的杀菌化合物进行细胞筛选，我们发现金诺芬（一种 FDA 批准的口服生物可用抗风湿药物）对复制型和非复制型结核分枝杆菌均具有有效的杀菌活性。我们还发现金诺芬对其他革兰氏阳性菌具有活性，包括枯草芽孢杆菌和粪肠球菌，以及屎肠球菌和金黄色葡萄球菌的药物敏感和耐药菌株。我们的生化研究表明，金诺芬抑制细菌硫氧还蛋白还原酶，这是许多革兰氏阳性细菌中维持硫醇-氧化还原平衡和防止活性氧化物质所必需的蛋白质。金诺芬降低目标细菌的还原能力，从而使它们对氧化应激敏感。最后，金诺芬在耐甲氧西林金黄色葡萄球菌感染的小鼠模型中有效。这些结果表明，硫氧还蛋白介导的革兰氏阳性病原体的氧化还原级联是开发抗菌药物的有效靶点，并且现有的临床药物金诺芬可以重新利用，以帮助治疗几种重要的抗生素耐药病原体。
Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell-based screen for bactericidal compounds against Mycobacterium tuberculosis under nutrient-deprivation conditions we identified auranofin, an orally bioavailable FDA-approved antirheumatic drug, as having potent bactericidal activities against both replicating and nonreplicating M. tuberculosis. We also found that auranofin is active against other Gram-positive bacteria, including Bacillus subtilis and Enterococcus faecalis, and drug-sensitive and drug-resistant strains of Enterococcus faecium and Staphylococcus aureus. Our biochemical studies showed that auranofin inhibits the bacterial thioredoxin reductase, a protein essential in many Gram-positive bacteria for maintaining the thiol-redox balance and protecting against reactive oxidative species. Auranofin decreases the reducing capacity of target bacteria, thereby sensitizing them to oxidative stress. Finally, auranofin was efficacious in a murine model of methicillin-resistant S. aureus infection. These results suggest that the thioredoxin-mediated redox cascade of Gram-positive pathogens is a valid target for the development of antibacterial drugs, and that the existing clinical agent auranofin may be repurposed to aid in the treatment of several important antibiotic-resistant pathogens.