Biological activities of novel gyrase inhibitors of the aminocoumarin class
Biological activities of novel gyrase inhibitors of the aminocoumarin class
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DOI：
10.1128/aac.01235-07
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发表时间：
2008-06-01
影响因子：
4.9
通讯作者：
Heide, Lutz
中科院分区：
文献类型：
--
作者：
Anderle, Christine;Stieger, Martin;Heide, Lutz
研究了来自诱变合成实验的 31 种氨基香豆素抗生素的生物活性。它们对大肠杆菌 DNA 旋转酶的抑制活性通过两种不同的体外测定进行测定：ATP 酶测定和 DNA 超螺旋测定。尽管每次测定中获得的绝对 50% 抑制浓度 (IC50S) 不同，但这些测定给出了所测试化合物的活性的相似排序。为了证实这些化合物在体内也起到旋转酶抑制剂的作用，通过使用与 luxCDABE 操纵子融合的 gyrA 和 sulA 启动子，对大肠杆菌进行了报告基因测定。对于在生化测定中显示旋转酶抑制活性的那些化合物，观察到两种启动子的强烈诱导。携带氯生菌素异戊二烯化苯甲酰基部分（A环）类似物的化合物在结构上非常不同，在生化测定和报告基因测定中均显示出高水平的活性，表明该部分的结构可以发生很大变化，而不会损失对细菌促旋酶的亲和力。将实验测定的IC50S与计算机计算的结合能进行比较，这表明吡咯羧酸部分从脱氧糖部分的O-3''位置到O-2''位置的转变对化合物的结合模式具有显着影响。还研究了氨基香豆素化合物对不同细菌病原体的 MIC。几种化合物显示出高水平的抗葡萄球菌活性，包括耐甲氧西林金黄色葡萄球菌菌株。然而，它们对革兰氏阴性菌株仅表现出较差的活性。
Thirty-one aminocoumarin antibiotics derived from mutasynthesis experiments were investigated for their biological activities. Their inhibitory activities toward Escherichia coli DNA gyrase were determined in two different in vitro assays: an ATPase assay and a DNA supercoiling assay. The assays gave a similar rank order of the activities of the compounds tested, although the absolute 50% inhibitory concentrations (IC50S) obtained in each assay were different. To confirm that the compounds also acted as gyrase inhibitors in vivo, reporter gene assays were carried out with E. coli by using gyrA and sulA promoter fusions with the luxCDABE operon. A strong induction of both promoters was observed for those compounds that showed gyrase inhibitory activity in the biochemical assays. Compounds carrying analogs of the prenylated benzoyl moiety (ring A) of clorobiocin that were structurally very different showed high levels of activity both in the biochemical assay and in the reporter gene assay, indicating that the structure of this moiety can be varied considerably without a loss of affinity for bacterial gyrase. The experimentally determined IC50S were compared to the binding energies calculated in silico, which indicated that a shift of the pyrrole carboxylic acid moiety from the O-3 '' to the O-2 '' position of the deoxysugar moiety has a significant impact on the binding mode of the compounds. The aminocoumarin compounds were also investigated for their MICs against different bacterial pathogens. Several compounds showed high levels of activity against staphylococci, including a methicillin-resistant Staphylococcus aureus strain. However, they showed only poor activities against gram-negative strains.