Combatting AMR: photoactivatable ruthenium(ii)-isoniazid complex exhibits rapid selective antimycobacterial activity. Issue 1 (30th August 2016)

• Record Type: Journal Article
• Authors: Smith, Nichola A.; Zhang, Pingyu; Greenough, Simon E.; Horbury, Michael D.; Clarkson, Guy J.; McFeely, Daniel; Habtemariam, Abraha; Salassa, Luca; Stavros, Vasilios G.; Dowson, Christopher G.; Sadler, Peter J.
• Is Part Of: Chemical science. Volume 8:Issue 1(2017)
• Page Start: 395
• Page End: 404
• Publication Date: 2016-08-30
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c6sc03028a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : 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). 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 (H2 O)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. Complex1 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 3 MC state. Importantly, complex1 is highly selective in killing mycobacteria versus normal human cells, towards which it is relatively non-toxic. This work suggests that photoactivatable prodrugs such as1 are potentially powerful new agents in combatting the global problem of antibiotic resistance.