Targeting synthesis of the Chromosome Replication Initiator Protein DnaA by antisense PNA-peptide conjugates in Escherichia coli

Christopher Campion, Godefroid Charbon, Peter E. Nielsen, A. Løbner‐Olesen
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Abstract

Initiation of chromosome replication is an essential stage of the bacterial cell cycle that is controlled by the DnaA protein. With the aim of developing novel antimicrobials, we have targeted the initiation of DNA replication, using antisense peptide nucleic acids (PNAs), directed against DnaA translation. A series of anti-DnaA PNA conjugated to lysine-rich bacterial penetrating peptides (PNA-BPPs) were designed to block DnaA translation. These anti-DnaA PNA-BPPs inhibited growth of wild-type Escherichia coli cells at low micromolar concentrations, and cells exposed to anti-DnaA PNA-BPPs exhibited characteristic hallmarks of chromosome replication inhibition. These results present one of very few compounds successfully targeting initiation of chromosome replication, an essential step in the bacterial cell cycle.
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在大肠杆菌中利用反义 PNA 肽共轭物靶向合成染色体复制启动蛋白 DnaA
染色体复制的启动是细菌细胞周期的一个重要阶段,由 DnaA 蛋白控制。为了开发新型抗菌药物,我们利用针对 DnaA 翻译的反义肽核酸 (PNA),以 DNA 复制的启动为目标。我们设计了一系列与富含赖氨酸的细菌穿透肽(PNA-BPPs)连接的抗 DnaA PNA,以阻断 DnaA 翻译。这些抗 DnaA PNA-BPPs 在低微摩尔浓度下抑制了野生型大肠杆菌细胞的生长,暴露于抗 DnaA PNA-BPPs 的细胞表现出染色体复制抑制的特征。这些结果是成功靶向启动染色体复制的极少数化合物之一,而染色体复制是细菌细胞周期的一个重要步骤。
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