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Combatting AMR : photoactivatable ruthenium(ii)-isoniazid complex exhibits rapid selective antimycobacterial activity
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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. and Sadler, P. J. (2016) Combatting AMR : photoactivatable ruthenium(ii)-isoniazid complex exhibits rapid selective antimycobacterial activity. Chemical Science, 8 (1). pp. 395-404. doi:10.1039/C6SC03028A ISSN 2041-6520.
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Official URL: http://dx.doi.org/10.1039/C6SC03028A
Abstract
The novel photoactive ruthenium(II) complex cis-[Ru(bpy)2(INH)2][PF6]2 (1ยท2PF6, 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 5.5ร 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.
Item Type: | Journal Article | ||||||||||
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Subjects: | Q Science > QR Microbiology R Medicine > RC Internal medicine |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
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Library of Congress Subject Headings (LCSH): | Drug resistance in microorganisms, Antitubercular agents, Isoniazid | ||||||||||
Journal or Publication Title: | Chemical Science | ||||||||||
Publisher: | Royal Society of Chemistry | ||||||||||
ISSN: | 2041-6520 | ||||||||||
Official Date: | 2016 | ||||||||||
Dates: |
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Volume: | 8 | ||||||||||
Number: | 1 | ||||||||||
Page Range: | pp. 395-404 | ||||||||||
DOI: | 10.1039/C6SC03028A | ||||||||||
Status: | Peer Reviewed | ||||||||||
Publication Status: | Published | ||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||
Date of first compliant deposit: | 31 August 2016 | ||||||||||
Date of first compliant Open Access: | 31 August 2016 | ||||||||||
Funder: | European Research Council (ERC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Engineering and Physical Sciences Research Council (EPSRC) | ||||||||||
Grant number: | 247450 (ERC), EP/F034210 (EPSRC) |
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