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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.Carbon monoxide (CO)-releasing molecules (CORMs) are used to deliver CO, a biological ‘gasotransmitter’, in biological chemistry and biomedicine. CORMs kill bacteria in culture and in animal models, but are reportedly benign towards mammalian cells. CORM-2 (tricarbonyldichlororuthe-nium(II) dimer, Ru2Cl4(CO)6 ), the first widely used and commercially available CORM, displays numerous pharmacological, biochemical and microbiological activities, generally attributed to CO release. Here, we investigate the basis of its potent antibacterial activity against Escherichia coli and demonstrate, using three globin CO sensors, that CORM-2 releases negligible CO (<0.1 mol CO per mol CORM-2). A strong negative correlation between viability and cellular ruthenium accumulation implies that ruthenium toxicity underlies biocidal activity. Exogenous amino acids and thiols (especially cysteine, glutathione and N-acetyl cysteine) protected bacteria against inhibition of growth by CORM-2. Bacteria treated with 30 µM CORM-2, with added cysteine and histidine, exhibited no significant loss of viability, but were killed in the absence of these amino acids. Their pre-vention of toxicity correlates with their CORM-2-binding affinities (Cys, Kd 3 µM; His, Kd 130 µM) as determined by1H-NMR. Glutathione is proposed to be an important intracellular target of CORM-2, with CORM-2 having a much higher affinity for reduced glutathione (GSH) than oxidised glutathione (GSSG) (GSH, Kd 2 µM; GSSG, Kd 25,000 µM). The toxicity of low, but potent, levels (15 µM) of CORM-2 was accompanied by cell lysis, as judged by the release of cytoplasmic ATP pools. The biological effects of CORM-2 and related CORMs, and the design of biological experiments, must be re-examined in the light of these data.
Author(s): Southam HM, Williamson MP, Chapman JA, Lyon RL, Trevitt CR, Henderson PJF, Poole RK, Antony A
Publication type: Article
Publication status: Published
Journal: Antioxidants
Year: 2021
Volume: 10
Issue: 6
Online publication date: 05/06/2021
Acceptance date: 02/06/2021
Date deposited: 14/06/2021
ISSN (electronic): 2076-3921
Publisher: MDPI AG
URL: https://doi.org/10.3390/antiox10060915
DOI: 10.3390/antiox10060915
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