Selective in vivo and in vitro activities of 3,3'-4-nitrobenzylidene-bis-4-hydroxycoumarin against methicillin-resistant Staphylococcus aureus by inhibition of DNA polymerase III.
Selective in vivo and in vitro activities of 3,3'-4-nitrobenzylidene-bis-4-hydroxycoumarin against methicillin-resistant Staphylococcus aureus by inhibition of DNA polymerase III.
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DOI：
10.1038/srep13637
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发表时间：
2015-09-01
影响因子：
4.6
通讯作者：
Luo X
中科院分区：
文献类型：
--
作者：
Hou Z;Zhou Y;Li J;Zhang X;Shi X;Xue X;Li Z;Ma B;Wang Y;Li M;Luo X
由于金黄色葡萄球菌对现有抗生素的持久耐药性与较高的感染率、死亡率和治疗费用有关，因此必须开发具有创新治疗靶点的新型抗菌药物。双香豆素衍生物3，3′-(4-Nitrobenzylidene)-bis-(4-hydroxycoumarin)(NBH)被报道具有抗菌活性。本研究探讨了NBH体内外抗金黄色葡萄球菌的作用机制。NBH对金黄色葡萄球菌和表皮葡萄球菌有较强的体外杀菌作用，细胞毒性和耐药性低，血浆稳定性高。NBH对败血症小鼠也有体内治疗作用。分子对接和形态变化、DNA合成及聚合酶抑制分析结果表明，DNA聚合酶可能是NBH的靶点。这些发现表明，干扰DNA复制的双香豆素衍生物可以作为一种潜在的药物来对抗金黄色葡萄球菌，特别是耐甲氧西林的菌株。
As the persistent resistance of Staphylococcus aureus to available antibiotics is associated with high infection incidence, mortality rate and treatment cost, novel antibacterial agents with innovative therapeutic targets must be developed. 3,3′-(4-Nitrobenzylidene)-bis-(4-hydroxycoumarin) (NBH), a dicoumarin derivative, was reported to exert antibacterial activity. This study investigated the underlying mechanisms of in vivo and in vitro activities of NBH against S. aureus. NBH exerted bactericidal effects against the tested S. aureus and Staphylococcus epidermidis strains in vitro, with low cytotoxicity and resistance and high plasma stability. NBH also exhibited therapeutic effects in vivo on septicaemic mice. Results of molecular docking and analysis on morphological change, DNA production and polymerase inhibition suggested that DNA polymerase could be the target of NBH. These findings indicated that dicoumarin derivatives, which interfere with DNA replication, could be developed as a potential agent against S. aureus, particularly methicillin-resistant strains.