Abstract
The bacterial primase—an essential component in the replisome—is a promising but underexploited target for novel antibiotic drugs. Bacterial primases have a markedly different structure than the human primase. Inhibition of primase activity is expected to selectively halt bacterial DNA replication. Evidence is growing that halting DNA replication has a bacteriocidal effect. Therefore, inhibitors of DNA primase could provide antibiotic agents. Compounds that inhibit bacterial DnaG primase have been developed using different approaches. In this paper, we provide an overview of the current literature on DNA primases as novel drug targets and the methods used to find their inhibitors. Although few inhibitors have been identified, there are still challenges to develop inhibitors that can efficiently halt DNA replication and may be applied in a clinical setting.
Highlights
The complex process of identifying antibacterial compounds begins with the selection of potential targets, which must be essential, selective over human homologues, susceptible to drugs, and have a low propensity to develop a rapid resistance [1]
The potential of making DNA primase a clinical target for novel antibiotics is high, but has not resulted in an increase of the repertoire of clinical candidates that could be especially beneficial against drug-resistant bacteria
Since the SSB-Ct binding pocket is present in other proteins besides DnaG and often mediates interactions that are necessary for bacterial survival, it represents an excellent target for new antibacterial agents [66]
Summary
The complex process of identifying antibacterial compounds begins with the selection of potential targets, which must be essential, selective over human homologues, susceptible to drugs, and have a low propensity to develop a rapid resistance [1]. A replisome is a multi-enzyme complex that synthesizes DNA continuously on its leading strand and discontinuously on its lagging strand [3,4]. Within a replisome of every living cell, DNA primase is an essential component that synthesizes short RNA primers that are used by DNA polymerase to form the “Okazaki fragments” on the lagging DNA strand [5]. The inhibition of primase is expected to halt DNA replication and, as a result, cell proliferation. The potential of making DNA primase a clinical target for novel antibiotics is high, but has not resulted in an increase of the repertoire of clinical candidates that could be especially beneficial against drug-resistant bacteria. The challenges in finding ways to inhibit primase are discussed along with the current drug discovery tools that have been used to develop novel and effective inhibitors. Examples of currently available primase inhibitors are provided as well
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