title: Ru(CO)3Cl(Glycinate) (CORM-3): a carbon monoxide-releasing molecule with broad-spectrum antimicrobial and photosensitive activities against respiration and cation transport in Escherichia coli.
abstract: OBJECTIVE
  Carbon monoxide (CO) delivered to cells and tissues by CO-releasing molecules (CO-RMs) has beneficial and toxic effects not mimicked by CO gas. The metal carbonyl Ru(CO)3Cl(glycinate) (CORM-3) is a novel, potent antimicrobial agent. Here, we established its mode of action.
  
  
  RESULTS
  CORM-3 inhibits respiration in several bacterial and yeast pathogens. In anoxic Escherichia coli suspensions, CORM-3 first stimulates, then inhibits respiration, but much higher concentrations of CORM-3 than of a classic protonophore are required for stimulation. Proton translocation measurements (H(+)/O quotients, i.e., H(+) extrusion on pulsing anaerobic cells with O2) show that respiratory stimulation cannot be attributed to true "uncoupling," that is, dissipation of the protonmotive force, or to direct stimulation of oxidase activity. Our data are consistent with CORM-3 facilitating the electrogenic transmembrane movement of K(+) (or Na(+)), causing a stimulation of respiration and H(+) pumping to compensate for the transient drop in membrane potential (ΔΨ). The effects on respiration are not mimicked by CO gas or control Ru compounds that do not release CO. Inhibition of respiration and loss of bacterial viability elicited by CORM-3 are reversible by white light, unambiguously identifying heme-containing oxidase(s) as target(s).
  
  
  METHODS
  This is the most complete study to date of the antimicrobial action of a CO-RM. Noteworthy are the demonstration of respiratory stimulation, electrogenic ion transport, and photosensitive activity, establishing terminal oxidases and ion transport as primary targets.
  
  
  CONCLUSIONS
  CORM-3 has multifaceted effects: increased membrane permeability, inhibition of terminal oxidases, and perhaps other unidentified mechanisms underlie its effectiveness in tackling microbial pathogenesis.
authors.affiliation: Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom.
authors.forename: Jayne Louise
authors.initials: JL
authors.lastname: Wilson
authors.forename: Helen E
authors.initials: HE
authors.lastname: Jesse
authors.forename: Bethan
authors.initials: B
authors.lastname: Hughes
authors.forename: Victoria
authors.initials: V
authors.lastname: Lund
authors.forename: Kathryn
authors.initials: K
authors.lastname: Naylor
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Davidge
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cook
authors.forename: Brian E
authors.initials: BE
authors.lastname: Mann
authors.forename: Robert K
authors.initials: RK
authors.lastname: Poole
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000737:chemistry*; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide