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Wareham, L.K., McLean, S. 
ORCID: 0000-0001-8551-4307, Begg, R., Rana, N., Ali, S., Kendall, J.J., Sanguinetti, G., Mann, B.E. and Poole, R.K.,
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 & Redox Signaling, 28 (14), pp. 1286-1308.
ISSN 1523-0864
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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.
| Item Type: | Journal article | ||||||
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| Publication Title: | Antioxidants & Redox Signaling | ||||||
| Creators: | Wareham, L.K., McLean, S., Begg, R., Rana, N., Ali, S., Kendall, J.J., Sanguinetti, G., Mann, B.E. and Poole, R.K. | ||||||
| Publisher: | Mary Ann Liebert, Inc. | ||||||
| Date: | 10 May 2018 | ||||||
| Volume: | 28 | ||||||
| Number: | 14 | ||||||
| ISSN: | 1523-0864 | ||||||
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| Divisions: | Schools > School of Science and Technology | ||||||
| Record created by: | Linda Sullivan | ||||||
| Date Added: | 18 Dec 2017 12:10 | ||||||
| Last Modified: | 20 Jan 2021 15:51 | ||||||
| URI: | https://irep.ntu.ac.uk/id/eprint/32201 |
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