Epstein Tessa D, Wu Bin, Moulton Karen D, Yan Mingdi, Dube Danielle H
Department of Chemistry & Biochemistry , Bowdoin College , 6600 College Station , Brunswick , Maine 04011 , United States.
Department of Chemistry , University of Massachusetts Lowell , 1 University Avenue , Lowell , Massachusetts 01854 , United States.
ACS Infect Dis. 2019 Oct 11;5(10):1682-1687. doi: 10.1021/acsinfecdis.9b00251. Epub 2019 Sep 9.
() infection poses a worldwide public health crisis, as chronic infection is rampant and can lead to gastric ulcers, gastritis, and gastric cancer. Unfortunately, frontline therapies cause harmful side effects and are often ineffective due to antibiotic resistance. The FDA-approved drug auranofin is a gold complex with a Au(I) core coordinated with triethylphosphine and peracetylated thioglucose as the ligands. Auranofin is used for the treatment of rheumatoid arthritis and also displays potent activity against . One of auranofin's modes of action involves cell death by disrupting cellular thiol-redox balance maintained by thioredoxin reductase (TrxR), but this disruption leads to unwanted side effects due to mammalian cell toxicity. Here, we developed and tested sugar-modified analogs of auranofin as potential antibiotics against , with the rationale that modulating the sugar moiety would bias uptake by targeting bacterial cells and mitigating mammalian cell toxicity. Sugar-modified auranofin analogs displayed micromolar minimum inhibitory concentrations against , maintained nanomolar inhibitory activity against the target enzyme TrxR, and caused reduced toxicity to mammalian cells. Taken together, our results suggest that structurally modifying the sugar component of auranofin has the potential to yield superior antibiotics for the treatment of infection. Broadly, glyco-tailoring is an attractive approach for repurposing approved drugs.
（）感染构成了一场全球公共卫生危机，因为慢性感染猖獗，可导致胃溃疡、胃炎和胃癌。不幸的是，一线治疗会产生有害的副作用，而且由于抗生素耐药性，往往无效。美国食品药品监督管理局（FDA）批准的药物金诺芬是一种金配合物，其Au（I）核心与三乙膦和全乙酰化硫代葡萄糖作为配体配位。金诺芬用于治疗类风湿性关节炎，也对 显示出强大的活性。金诺芬的作用模式之一涉及通过破坏由硫氧还蛋白还原酶（TrxR）维持的细胞硫醇-氧化还原平衡导致细胞死亡，但这种破坏由于哺乳动物细胞毒性而导致不良副作用。在这里，我们开发并测试了金诺芬的糖修饰类似物作为针对 的潜在抗生素，其基本原理是调节糖部分将通过靶向细菌细胞和减轻哺乳动物细胞毒性来偏向摄取。糖修饰的金诺芬类似物对 显示出微摩尔级的最低抑菌浓度，对靶酶TrxR保持纳摩尔级的抑制活性，并对哺乳动物细胞造成降低的毒性。综上所述，我们的结果表明，对金诺芬的糖成分进行结构修饰有可能产生用于治疗 感染的优质抗生素。广泛地说，糖基定制是一种用于重新利用已批准药物的有吸引力的方法。
