Effects of 4-Br-A23187 on Bacillus subtilis cells and unilamellar vesicles reveal it to be a potent copper ionophore.
Effects of 4-Br-A23187 on Bacillus subtilis cells and unilamellar vesicles reveal it to be a potent copper ionophore.
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离子载体是通过生物膜运输金属离子的小分子或多肽。它们的运输能力通常在体外使用囊泡和单离子物种进行表征。从这些数据中很难推断出离子载体在复杂环境（例如培养基）中对活细胞的影响，因为净离子运动受到许多因素的影响，包括介质的离子组成、浓度梯度、pH梯度和蛋白质介导的跨膜运输过程。为了深入了解半合成聚醚离子载体4-Br-A23187的抑菌机制，我们研究了它对革兰氏阳性模式生物枯草芽孢杆菌的作用。除了监测细胞离子浓度外，还在蛋白质组水平上评估了治疗的生理影响。4-Br-A23187处理导致细胞内铜水平升高，其程度取决于培养基中的铜浓度。蛋白质组学反应反映的铜积累影响包括氧化应激、蛋白质平衡紊乱、金属和硫稳态紊乱。4-Br-A23187的抗生素作用因细胞内锰和镁的减少而进一步增强。脂质体模型证实了4-Br-A23187在体外作为铜离子载体的作用。
Ionophores are small molecules or peptides that transport metal ions across biological membranes. Their transport capabilities are typically characterized in vitro using vesicles and single ion species. It is difficult to infer from these data which effects ionophores have on living cells in a complex environment (e.g., culture medium), since net ion movement is influenced by many factors including ion composition of the medium, concentration gradients, pH gradient, and protein-mediated transport processes across the membrane. To gain insights into the antibacterial mechanism of action of the semisynthetic polyether ionophore 4-Br-A23187, known to efficiently transport zinc and manganese in vitro, we investigated its effects on the gram-positive model organism Bacillus subtilis. In addition to monitoring cellular ion concentrations, the physiological impact of treatment was assessed on the proteome level. 4-Br-A23187 treatment resulted in an increase in intracellular copper levels, the extent of which depended on the copper concentration of the medium. Effects of copper accumulation mirrored by the proteomic response included oxidative stress, disturbance of proteostasis, metal and sulfur homeostasis. The antibiotic effect of 4-Br-A23187 is further aggravated by a decrease in intracellular manganese and magnesium. A liposome model confirmed that 4-Br-A23187 acts as copper ionophore in vitro.
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