Wang Peng, Wang Jun, Xie Zonglan, Zhou Jingxuan, Lu Qianqian, Zhao Ying, Dong Chuanjiang, Zou Lili
The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, China.
The Institute of Infection and Inflammation, Medical College, China Three Gorges University, Yichang, Hubei, China.
J Cell Mol Med. 2020 Nov;24(22):13139-13150. doi: 10.1111/jcmm.15920. Epub 2020 Sep 25.
Ebselen, an organo-selenium compound with well-characterized toxicology and pharmacology, recently exhibited potent antibacterial activity against glutathione (GSH)-negative bacteria by disrupting redox homeostasis. In this paper, we show that ebselen and silver ion in combination exert strong bactericidal activity against multidrug-resistant (MDR) uropathogenic Escherichia coli (UPEC) BC1, a model MDR GSH-positive bacterium. The mechanisms were found to involve consumption of total intracellular GSH and inhibition of thioredoxin reductase activity, which was highly related to reactive oxygen species up-regulation. Furthermore, the therapeutic efficacy of ebselen and silver ion against UPEC-induced cystitis was assessed in a mouse model. Treatment with ebselen and silver ion significantly reduced bacterial loads, down-regulated the expression levels of tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) on-site and decreased white/red blood cell counts in mild cystitis model mice, which demonstrated the anti-inflammatory property of these agents. In addition, ebselen and silver ion also exhibited significantly high protective ability (100%) against acute cystitis infections. These results together may lay the foundation for further analysis and development of ebselen and silver ion as antibacterial agents for treatment of MDR UPEC infections.
依布硒啉是一种具有明确毒理学和药理学特性的有机硒化合物，最近通过破坏氧化还原稳态，对谷胱甘肽（GSH）阴性细菌表现出强大的抗菌活性。在本文中，我们表明依布硒啉与银离子联合使用，对多重耐药（MDR）尿路致病性大肠杆菌（UPEC）BC1（一种典型的MDR GSH阳性细菌）具有强大的杀菌活性。研究发现其作用机制包括消耗细胞内总GSH以及抑制硫氧还蛋白还原酶活性，这与活性氧上调高度相关。此外，在小鼠模型中评估了依布硒啉和银离子对UPEC诱导的膀胱炎的治疗效果。在轻度膀胱炎模型小鼠中，依布硒啉和银离子治疗显著降低了细菌载量，下调了肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的现场表达水平，并降低了白细胞/红细胞计数，这证明了这些药物的抗炎特性。此外，依布硒啉和银离子对急性膀胱炎感染也表现出显著的高保护能力（100%）。这些结果共同为进一步分析和开发依布硒啉和银离子作为治疗MDR UPEC感染的抗菌药物奠定了基础。
