Combatting AMR: photoactivatable ruthenium(ii)-isoniazid complex exhibits rapid selective antimycobacterial activity.
Combatting AMR: photoactivatable ruthenium(ii)-isoniazid complex exhibits rapid selective antimycobacterial activity.
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DOI：
10.1039/c6sc03028a
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发表时间：
2017-01-01
期刊：
影响因子：
8.4
通讯作者：
Sadler PJ
中科院分区：
文献类型：
--
作者：
Smith NA;Zhang P;Greenough SE;Horbury MD;Clarkson GJ;McFeely D;Habtemariam A;Salassa L;Stavros VG;Dowson CG;Sadler PJ
Ru（ii）配合物cis-[Ru（bpy）2（INH）2]2+在黑暗中无活性，但在可见光下对分枝杆菌具有高度活性，当其释放抗结核药物异烟肼（INH）时。新型光活性钌配合物cis-[Ru（bpy）2（INH）2][PF 6]2（1·2 PF 6，INH =异烟肼）被设计用于掺入抗结核药物异烟肼，其可以通过可见光的光活化从Ru（ii）笼中释放。在465 nm蓝光照射下，1在水溶液中迅速释放出2当量的异烟肼，并生成光产物cis-[Ru（bpy）2（H2O）2]2+。我们使用蓝色和多色LED多孔阵列在体外筛选了对含有三种主要细胞包膜的细菌的活性：革兰氏阳性枯草芽孢杆菌、革兰氏阴性大肠杆菌和耻垢分枝杆菌。配合物1在黑暗中无活性，但当光活化时，对M的效力提高5.5倍。与单独的临床药物异烟肼相比，互补泵浦-探测光谱测量沿着与密度泛函理论计算揭示，单水合产物形成在<500 ps，可能是由3 MC状态促进。重要的是，复合物1在杀死分枝杆菌方面相对于正常人细胞具有高度选择性，而对正常人细胞相对无毒。这项工作表明，可光活化的前药，如1是潜在的强大的新药剂，在打击全球性的抗生素耐药性问题。
The Ru(ii) complex, cis-[Ru(bpy)2(INH)2]2+ is inactive in the dark but highly active towards mycobacteria on photoactivation with visible light when it releases the antituberculosis drug isoniazid (INH). The novel photoactive ruthenium(ii) complex cis-[Ru(bpy)2(INH)2][PF6]2 (1·2PF6, INH = isoniazid) was designed to incorporate the anti-tuberculosis drug, isoniazid, that could be released from the Ru(ii) cage by photoactivation with visible light. In aqueous solution, 1 rapidly released two equivalents of isoniazid and formed the photoproduct cis-[Ru(bpy)2(H2O)2]2+ upon irradiation with 465 nm blue light. We screened for activity against bacteria containing the three major classes of cell envelope: Gram-positive Bacillus subtilis, Gram-negative Escherichia coli, and Mycobacterium smegmatis in vitro using blue and multi-colored LED multi-well arrays. Complex 1 is inactive in the dark, but when photoactivated is 5.5× more potent towards M. smegmatis compared to the clinical drug isoniazid alone. Complementary pump-probe spectroscopy measurements along with density functional theory calculations reveal that the mono-aqua product is formed in <500 ps, likely facilitated by a 3MC state. Importantly, complex 1 is highly selective in killing mycobacteria versus normal human cells, towards which it is relatively non-toxic. This work suggests that photoactivatable prodrugs such as 1 are potentially powerful new agents in combatting the global problem of antibiotic resistance.