Isoprenoid biosynthesis as a drug target:: Bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin
Isoprenoid biosynthesis as a drug target:: Bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin
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DOI：
10.1021/jm060492b
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发表时间：
2006-12-14
影响因子：
7.3
通讯作者：
Oldfield, Eric
中科院分区：
文献类型：
--
作者：
Leon, Annette;Liu, Lei;Oldfield, Eric
我们筛选了117个双膦酸盐对大肠杆菌的抗菌活性库。最有效的生长抑制剂是N-[甲基（4-苯基烷基）]-3-氨丙基-1-羟基-1，1-二膦酸盐，已知有效的骨吸收抑制剂，并且细胞生长抑制与E.大肠杆菌法呢基二磷酸合成酶（FPPS）抑制。然而，一些有效的FPPS抑制剂在细胞生长抑制中没有活性，根据催化剂药效团建模的结果，这可能归因于细胞活性需要大的疏水性特征（由于最有可能转运）。最有效的化合物N-[甲基（4-苯基丁基）]-3-氨丙基-1-羟基-1，1-二膦酸盐（13）的活性被药物磷咪霉素强烈增强。单独的13或磷酰胺霉素的转录谱与单独的羧苄青霉素或环丙沙星的转录谱不同，但组合（13-磷酰胺霉素）与羧苄青霉素或环丙沙星之间有许多相似之处，反映了药物组合对细菌生长的更有效的杀菌活性。
We screened a library of 117 bisphosphonates for antibacterial activity against Escherichia coli. The most potent growth inhibitors where the N-[methyl(4-phenylalkyl)]-3-aminopropyl-1-hydroxy-1,1-bisphosphonates, known potent bone resorption inhibitors, and there was a generally good correlation between cell growth inhibition and E. coli farnesyl diphosphate synthase (FPPS) inhibition. However, some potent FPPS inhibitors had no activity in cell growth inhibition, and based on the result of Catalyst pharmacophore modeling, this could be attributed to the requirement of a large hydrophobic feature for cellular activity (due most likely to transport). The activity of the most potent compound, N-[methyl(4-phenylbutyl)]-3-aminopropyl-1-hydroxy1,1-bisphosphonate (13), was strongly potentiated by the drug fosmidomycin. The transcription profiles for 13 or fosmidomycin alone were different from those found with carbenicillin or ciprofloxacin alone, but there were many similarities between the combination (13-fosmidomycin) and carbenicillin or ciprofloxacin, reflecting the more potent bactericidal activity of the drug combination on bacterial growth.