Santos Joana A, Lamers Meindert H
Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.
Antibiotics (Basel). 2020 Nov 4;9(11):776. doi: 10.3390/antibiotics9110776.
Multidrug resistance is a worldwide problem that is an increasing threat to global health. Therefore, the development of new antibiotics that inhibit novel targets is of great urgency. Some of the most successful antibiotics inhibit RNA transcription, RNA translation, and DNA replication. Transcription and translation are inhibited by directly targeting the RNA polymerase or ribosome, respectively. DNA replication, in contrast, is inhibited indirectly through targeting of DNA gyrases, and there are currently no antibiotics that inhibit DNA replication by directly targeting the replisome. This contrasts with antiviral therapies where the viral replicases are extensively targeted. In the last two decades there has been a steady increase in the number of compounds that target the bacterial replisome. In particular a variety of inhibitors of the bacterial replicative polymerases PolC and DnaE have been described, with one of the DNA polymerase inhibitors entering clinical trials for the first time. In this review we will discuss past and current work on inhibition of DNA replication, and the potential of bacterial DNA polymerase inhibitors in particular as attractive targets for a new generation of antibiotics.
多重耐药性是一个全球性问题，对全球健康构成日益严重的威胁。因此，开发抑制新靶点的新型抗生素迫在眉睫。一些最成功的抗生素可抑制RNA转录、RNA翻译和DNA复制。转录和翻译分别通过直接靶向RNA聚合酶或核糖体来抑制。相比之下，DNA复制是通过靶向DNA促旋酶间接抑制的，目前尚无通过直接靶向复制体来抑制DNA复制的抗生素。这与抗病毒疗法形成对比，在抗病毒疗法中病毒复制酶是广泛的靶点。在过去二十年中，靶向细菌复制体的化合物数量稳步增加。特别是已经描述了多种细菌复制性聚合酶PolC和DnaE的抑制剂，其中一种DNA聚合酶抑制剂首次进入临床试验。在这篇综述中，我们将讨论过去和当前关于抑制DNA复制的工作，特别是细菌DNA聚合酶抑制剂作为新一代抗生素有吸引力的靶点的潜力。
