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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Disrupting antibiotic resistance propagation by inhibiting the conjugative DNA relaxase
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Disrupting antibiotic resistance propagation by inhibiting the conjugative DNA relaxase

机译：通过抑制结合性DNA松弛酶破坏抗生素耐药性的传播

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摘要

Conjugative transfer of plasmid DNA via close cell-cell junctions is the main route by which antibiotic resistance genes spread between bacterial strains. Relaxases are essential for conjugative transfer and act by cleaving DNA strands and forming covalent phosphotyrosine linkages. Based on data indicating that multity-rosine relaxase enzymes can accommodate two phosphotyrosine intermediates within their divalent metal-containing active sites, we hypothesized that bisphosphonates would inhibit relaxase activity and conjugative DNA transfer. We identified bisphosphonates that are nanomolar inhibitors of the F plasmid conjugative relaxase in vitro. Furthermore, we used cell-based assays to demonstrate that these compounds are highly effective at preventing DNA transfer and at selectively killing cells harboring conjugative plasmids. Two potent inhibitors, clodronate and etidronate, are already clinically approved to treat bone loss. Thus, the inhibition of conjugative relaxases is a potentially novel antimicrobial approach, one that selectively targets bacteria capable of transferring antibiotic resistance and generating multidrug resistant strains.
机译：经由紧密的细胞间连接的质粒DNA的共轭转移是抗生素抗性基因在细菌菌株之间传播的主要途径。松弛酶对于共轭转移是必不可少的，并通过切割DNA链和形成共价磷酸酪氨酸键起作用。基于表明多酪氨酸松弛酶可以在其含二价金属的活性位点内容纳两个磷酸酪氨酸中间体的数据，我们假设双膦酸酯会抑制松弛酶活性和共轭DNA转移。我们确定双膦酸盐是体外F质粒结合松弛酶的纳摩尔抑制剂。此外，我们使用基于细胞的测定法来证明这些化合物在防止DNA转移和选择性杀死带有结合质粒的细胞方面非常有效。两种有效的抑制剂，氯膦酸盐和依替膦酸盐，已经在临床上被批准用于治疗骨质流失。因此，抑制结合松弛酶是一种潜在的新型抗菌方法，该方法选择性地靶向能够转移抗生素抗性并产生多药抗性菌株的细菌。

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