Edinburgh Research Explorer

The Broad-Spectrum Antimicrobial Potential of [Mn(CO)4S2CNMe(CH2CO2H)], a Water-Soluble CO-Releasing Molecule (CORM-401): Intracellular Accumulation, Transcriptomic and Statistical Analyses, and Membrane Polarization

Research output: Contribution to journalArticle

  • Lauren Wareham
  • Samantha McLean
  • Ronald Beqq
  • Namrata Rana
  • Salar Ali
  • John Kendall
  • Guido Sanguinetti
  • Brian Mann
  • Robert Poole

Related Edinburgh Organisations

Open Access permissions

Open

Documents

http://online.liebertpub.com/doi/10.1089/ars.2017.7239
Original languageEnglish
Number of pages66
JournalAntioxidants and Redox Signaling
Volume28
Issue number14
Early online date28 Sep 2017
DOIs
Publication statusPublished - 10 May 2018

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, Nigel Robinson.

Download statistics

No data available

ID: 41590340