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Issue 1, 2017
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Combatting AMR: photoactivatable ruthenium(II)-isoniazid complex exhibits rapid selective antimycobacterial activity

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Abstract

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.

Graphical abstract: Combatting AMR: photoactivatable ruthenium(ii)-isoniazid complex exhibits rapid selective antimycobacterial activity

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Publication details

The article was received on 09 Jul 2016, accepted on 11 Aug 2016 and first published on 30 Aug 2016


Article type: Edge Article
DOI: 10.1039/C6SC03028A
Citation: Chem. Sci., 2017,8, 395-404
  • Open access: Creative Commons BY license
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    Combatting AMR: photoactivatable ruthenium(II)-isoniazid complex exhibits rapid selective antimycobacterial activity

    N. A. Smith, P. Zhang, S. E. Greenough, M. D. Horbury, G. J. Clarkson, D. McFeely, A. Habtemariam, L. Salassa, V. G. Stavros, C. G. Dowson and P. J. Sadler, Chem. Sci., 2017, 8, 395
    DOI: 10.1039/C6SC03028A

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