Screening of inhibitors of DNA replication by using the oriC plasmid replication system of Escherichia coli

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DnaA protein is the initiator of chromosomal DNA replication in Escherichia coli. The purpose of this study is a discovery of inhibitors of DNA replication in Escherichia coli by measurement of the inhibition of the ATP-binding to DnaA protein. Preliminary study by the group of the head investigator has shown that a derivative of indigo inhibits the ATP-binding activity of DnaA protein. In this study, we synthesized a number of indigo derivatives, and examined the relationship between their structures and inhibition of the ATP-binding to DnaA protein. We showed that alkyl residue is necessary for the activity. As a result, we could synthesize a compound which showed 50% inhibition at the concentration of 7muM.We further demonstrated that the compound specifically inhibited the initiation of DNA synthesis in an oriC plasmid DNA replication system. The results were published in J.Biol.Chem.in 1996.