Targeting antibacterial agents by using drug-carrying filamentous bacteriophages
Targeting antibacterial agents by using drug-carrying filamentous bacteriophages
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DOI：
10.1128/aac.00169-06
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发表时间：
2006-06-01
影响因子：
4.9
通讯作者：
Benhar, Itai
中科院分区：
文献类型：
--
作者：
Yacoby, Iftach;Shamis, Marina;Benhar, Itai
噬菌体用于（非常规）细菌感染治疗已有一个多世纪的历史，半个世纪以来，它被用作基因研究的工具；二十年来，噬菌体被用作发现特定靶标结合蛋白的工具；近十年来，噬菌体被用作疫苗接种工具或基因递送载体。在这里，我们提出了丝状噬菌体（噬菌体）作为靶向药物载体用于根除（致病）细菌的新应用。噬菌体经过基因改造，在其表面展示靶向部分，并用于向目标细菌递送大量细胞毒性药物。该药物通过受控释放的不稳定连接体通过化学缀合的方式与噬菌体连接。在缀合状态下，药物实际上是缺乏细胞毒活性的前药，并且在其以时间和空间受控方式在靶位点与噬菌体解离后被激活。我们的模型目标是金黄色葡萄球菌，模型药物是抗生素氯霉素。我们证明了使用丝状噬菌体作为疾病相关靶向细胞的通用药物载体的潜力。我们的方法用靶向部分所具有的靶点选择性取代了药物本身的选择性，这可能允许重新引入迄今为止被排除在抗菌用途之外的非特异性药物（由于毒性或选择性低）。将此类药物重新引入有用的工具库中可能有助于对抗新出现的细菌抗生素耐药性。
Bacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as targeted drug carriers for the eradication of (pathogenic) bacteria. The phages are genetically modified to display a targeting moiety on their surface and are used to deliver a large payload of a cytotoxic drug to the target bacteria. The drug is linked to the phages by means of chemical conjugation through a labile linker subject to controlled release. In the conjugated state, the drug is in fact a prodrug devoid of cytotoxic activity and is activated following its dissociation from the phage at the target site in a temporally and spatially controlled manner. Our model target was Staphylococcus aureus, and the model drug was the antibiotic chloramphenicol. We demonstrated the potential of using filamentous phages as universal drug carriers for targetable cells involved in disease. Our approach replaces the selectivity of the drug itself with target selectivity borne by the targeting moiety, which may allow the reintroduction of nonspecific drugs that have thus far been excluded from antibacterial use (because of toxicity or low selectivity). Reintroduction of such drugs into the arsenal of useful tools may help to combat emerging bacterial antibiotic resistance.