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首页> 外文期刊>Infectious disorders drug targets >Antimicrobials Targeted to the Replication-Specific DNA Polymerases of Gram-Positive Bacteria: Target Potential of dnaE.
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Antimicrobials Targeted to the Replication-Specific DNA Polymerases of Gram-Positive Bacteria: Target Potential of dnaE.

机译：靶向革兰氏阳性细菌的复制特异性DNA聚合酶的抗菌药物：dnaE的目标潜力。

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摘要

DNA polymerases pol IIIC and dnaE [i.e. pol IIIE] are essential for replicative DNA synthesis in low G:C Gram-positive eubacteria. Therefore, they have strong potential as targets for development of Gram-positive-selective antibacterial agents. This work has sought to extend to dnaE the recent discovery of antimicrobial agents based on pol IIICspecific dGTP analogs. Compound 324C, a member of the same dGTP analog family, was found to be a potent and selective inhibitor of isolated dnaE in vitro. Surprisingly, 324C had no inhibitory effect in either intact Bacillus subtilis cells or in permeabilized cell preparations used to assess replicative DNA synthesis directly. It is proposed that the failure of 324C in the intact cell is a consequence of two major factors: (i) its template-dependent base pairing mechanism, and (ii) a specific subordinate role which dnaE apparently plays to pol IIIC. To generate an effective dnaE-selective inhibitor of replicative DNA synthesis in Gram-positive bacteria, it will likely be necessary to develop a molecule that attacks the enzyme's active site directly, without binding to template DNA.
机译：DNA聚合酶pol IIIC和dnaE [即pol IIIE]对于低G：C革兰氏阳性真细菌的复制性DNA合成至关重要。因此，它们具有作为革兰氏阳性选择性抗菌剂开发目标的强大潜力。这项工作试图将基于pol IIIC特异性dGTP类似物的抗菌剂的最新发现扩展到dnaE。发现化合物324C是同一dGTP类似物家族的成员，是体外分离的dnaE的有效和选择性抑制剂。令人惊讶的是，324C在完整的枯草芽孢杆菌细胞或用于直接评估复制性DNA合成的透化细胞制备物中均没有抑制作用。有人提出，完整细胞中324C的失败是两个主要因素的结果：（i）其依赖模板的碱基配对机制，以及（ii）dnaE显然在pol IIIC中起特定的从属作用。为了在革兰氏阳性细菌中产生有效的复制DNA合成的dnaE选择性抑制剂，可能有必要开发一种直接攻击该酶活性位点而不结合模板DNA的分子。

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