Issue 1, 2017

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
09 Jul 2016
Accepted
11 Aug 2016
First published
30 Aug 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2017,8, 395-404

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

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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