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The novel photoactive ruthenium(ii) complex cis -[Ru(bpy) 2 (INH) 2 ][PF 6 ] 2 ( 1 ·2PF 6 , 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 (H 2 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. 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 &lt;500 ps, likely facilitated by a 3 MC 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.

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