Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin.
Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin.
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DOI：
10.1002/jobm.201200617
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发表时间：
2014-04
影响因子：
3.1
通讯作者：
Schönbrunn E
中科院分区：
文献类型：
--
作者：
Olesen SH;Ingles DJ;Yang Y;Schönbrunn E
土酸是土曲霉真菌产生的具有抗生素特性的代谢物，但其细胞靶点仍然未知。我们最近报道，土酸在体外通过与残基 Cys115 的共价反应灭活细菌细胞壁生物合成酶 MurA，其方式与 MurA 特异性抗生素磷霉素类似。为了确定土酸在体内是否也靶向 MurA，我们使用选定的大肠杆菌菌株与磷霉素平行进行了抗菌研究。虽然 MurA 的过度表达赋予了对磷霉素的抗性，但它并不能保护用土酸处理的细胞。此外，流式细胞术显示土酸的抗生素作用似乎主要是抑菌作用，这与磷霉素观察到的杀菌作用相反。综合起来，数据表明 MurA 不是土酸的分子靶标，并且土酸的抗生素活性通过不同的作用机制进行。这里应用的方法提供了一种可靠且方便的工具来快速评估新发现的体外抑制剂针对细胞中 MurA 残基 Cys115 的潜力。
Terreic acid is a metabolite with antibiotic properties produced by the fungus Aspergillus terreus, but its cellular target remains unknown. We recently reported that terreic acid inactivates the bacterial cell wall biosynthetic enzyme MurA in vitro by covalent reaction with residue Cys115 in a similar manner as the MurA-specific antibiotic fosfomycin. To address if terreic acid also targets MurA in vivo, we conducted antibacterial studies using selected E. coli strains in parallel with fosfomycin. While overexpression of MurA conferred resistance to fosfomycin, it did not protect cells treated with terreic acid. Furthermore, flow cytometry revealed that the antibiotic action of terreic acid appears to be primarily bacteriostatic, as opposed to the bactericidal action observed for fosfomycin. Combined, the data suggest that MurA is not the molecular target of terreic acid and that the antibiotic activity of terreic acid proceeds through a different mechanism of action. The methodology applied here provides a reliable and convenient tool to rapidly assess the potential of newly discovered in vitro inhibitors to target residue Cys115 of MurA in the cell.