University of Copenhagen, Dept. of Biology, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
University of Copenhagen, Dept. of Chemistry, Universitetsparken 5, 2100, Copenhagen Ø, Denmark.
Sci Rep. 2018 Jul 12;8(1):10550. doi: 10.1038/s41598-018-28841-9.
In Escherichia coli, an increase in the frequency of chromosome replication is lethal. In order to identify compounds that affect chromosome replication, we screened for molecules capable of restoring the viability of hyper-replicating cells. We made use of two E. coli strains that over-initiate DNA replication by keeping the DnaA initiator protein in its active ATP bound state. While viable under anaerobic growth or when grown on poor media, these strains become inviable when grown in rich media. Extracts from actinomycetes strains were screened, leading to the identification of deferoxamine (DFO) as the active compound in one of them. We show that DFO does not affect chromosomal replication initiation and suggest that it was identified due to its ability to chelate cellular iron. This limits the formation of reactive oxygen species, reduce oxidative DNA damage and promote processivity of DNA replication. We argue that the benzazepine derivate (±)-6-Chloro-PB hydrobromide acts in a similar manner.
在大肠杆菌中，染色体复制频率的增加是致命的。为了鉴定影响染色体复制的化合物，我们筛选了能够恢复超复制细胞活力的分子。我们利用两种能够使 DnaA 起始蛋白保持在其活性 ATP 结合状态的大肠杆菌菌株来过度启动 DNA 复制。虽然在厌氧生长或在贫瘠培养基上生长时具有活力，但当在丰富的培养基中生长时，这些菌株变得没有活力。筛选放线菌菌株的提取物，导致其中一种提取物中的去铁胺 (DFO) 被鉴定为活性化合物。我们表明 DFO 不影响染色体复制起始，并提出它被鉴定是因为它能够螯合细胞内的铁。这限制了活性氧物质的形成，减少了氧化 DNA 损伤，并促进了 DNA 复制的连续性。我们认为苯并氮杂衍生物（±）-6-氯-PB 氢溴酸盐以类似的方式起作用。
