Wareham, L.K., McLean, S., Begg, R. et al. (6 more authors) (2018) The broad-spectrum antimicrobial potential of [Mn(CO)4(S2CNMe(CH2CO2H))], a water-soluble CO-releasing molecule (CORM-401): intracellular accumulation, transcriptomic and statistical analyses, and membrane polarization. Antioxidants and Redox Signaling, 28 (14). pp. 1286-1308. ISSN 1523-0864
Abstract
AIMS: Carbon monoxide (CO)-releasing molecules (CORMs) are candidates for animal and antimicrobial therapeutics. We aimed to probe the antimicrobial potential of a novel manganese CORM. RESULTS: [Mn(CO)4S2CNMe(CH2CO2H)], CORM-401, inhibits growth of Escherichia coli and several antibiotic-resistant clinical pathogens. CORM-401 releases CO that binds oxidases in vivo, but is an ineffective respiratory inhibitor. Extensive CORM accumulation (assayed as intracellular manganese) accompanies antimicrobial activity. CORM-401 stimulates respiration, polarizes the cytoplasmic membrane in an uncoupler-like manner, and elicits loss of intracellular potassium and zinc. Transcriptomics and mathematical modeling of transcription factor activities reveal a multifaceted response characterized by elevated expression of genes encoding potassium uptake, efflux pumps, and envelope stress responses. Regulators implicated in stress responses (CpxR), respiration (Arc, Fnr), methionine biosynthesis (MetJ), and iron homeostasis (Fur) are significantly disturbed. Although CORM-401 reduces bacterial growth in combination with cefotaxime and trimethoprim, fractional inhibition studies reveal no interaction. INNOVATION: We present the most detailed microbiological analysis yet of a CORM that is not a ruthenium carbonyl. We demonstrate CO-independent striking effects on the bacterial membrane and global transcriptomic responses. CONCLUSIONS: CORM-401, contrary to our expectations of a CO delivery vehicle, does not inhibit respiration. It accumulates in the cytoplasm, acts like an uncoupler in disrupting cytoplasmic ion balance, and triggers multiple effects, including osmotic stress and futile respiration. Rebound Track: This work was rejected during standard peer review and rescued by rebound peer review (Antioxid Redox Signal 16:293-296, 2012) with the following serving as open reviewers: Miguel Aon, Giancarlo Biagini, James Imlay, and Nigel Robinson. Antioxid. Redox Signal. 00, 000-000.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 Lauren K. Wareham et al; Published by Mary Ann Liebert Inc Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | antibacterial agents; carbon monoxide-releasing molecule; manganese carbonyl compound; systems biology; uncoupling agent |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Molecular Biology and Biotechnology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 30 Nov 2017 13:43 |
Last Modified: | 10 Nov 2023 16:48 |
Status: | Published |
Publisher: | Mary Ann Liebert |
Refereed: | Yes |
Identification Number: | 10.1089/ars.2017.7239 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:124619 |