title: Differential antibacterial activity against Pseudomonas aeruginosa by carbon monoxide-releasing molecules.
abstract: OBJECTIVE
  Carbon monoxide (CO) delivered in a controlled manner to cells and organisms mediates a variety of pharmacological effects to the extent that CO-releasing molecules (CO-RMs) are being developed for therapeutic purposes. Recently, ruthenium-based CO-RMs have been shown to posses important bactericidal activity. Here we assessed the effect of fast CO releasers containing ruthenium (Ru(CO)(3)Cl(glycinate) [CORM-3] and tricarbonyldichlororuthenium(II) dimer [CORM-2]) and a novel slow manganese-based CO releaser ([Me(4)N][Mn(CO)(4)(thioacetate)(2)] [CORM-371]) on O(2) consumption and growth of Pseudomonas aeruginosa (PAO1). We then compared these effects with the action elicited by sodium boranocarbonate (CORM-A1), which lacks a transition metal but liberates CO with a rate similar to CORM-371.
  
  
  RESULTS
  CORM-2, CORM-3, and, to a lesser extent, CORM-371 exerted a significant bactericidal effect and decreased O(2) consumption in PAO1 in vitro. The effect appeared to be independent of reactive oxygen species production, but in the case of metal-containing compounds it was prevented by the thiol donor N-acetylcysteine. In contrast, CORM-A1 was bacteriostatic rather than bactericidal in vitro eliciting only a moderate and transient decrease in O(2) consumption.
  
  
  METHODS
  None of the tested CO-RMs was toxic to murine macrophages or human fibroblasts at the concentration impairing PA01 growth but only ruthenium-containing CO-RMs showed potential therapeutic properties by increasing the survival of mice infected with PA01.
  
  
  CONCLUSIONS
  CO carriers inhibit bacterial growth and O(2) consumption in vitro, but transition metal carbonyls appear more powerful than compounds spontaneously liberating CO. The nature of the metal in CO-RMs also modulates the anti-bacterial effect, with ruthenium-based CO-RMs being efficacious both in vitro and in vivo.
authors.affiliation: Université Paris Est, Creteil, France. desmardmathieu@yahoo.fr
authors.forename: Mathieu
authors.initials: M
authors.lastname: Desmard
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
authors.forename: Didier
authors.initials: D
authors.lastname: Morin
authors.forename: Maylis
authors.initials: M
authors.lastname: Dagouassat
authors.forename: Maylis
authors.initials: M
authors.lastname: Dagoussat
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.forename: Erick
authors.initials: E
authors.lastname: Denamur
authors.forename: Sian H
authors.initials: SH
authors.lastname: Crook
authors.forename: Brian E
authors.initials: BE
authors.lastname: Mann
authors.forename: David
authors.initials: D
authors.lastname: Scapens
authors.forename: Philippe
authors.initials: P
authors.lastname: Montravers
authors.forename: Jorge
authors.initials: J
authors.lastname: Boczkowski
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D010100:Oxygen / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D017382:Reactive Oxygen Species; D002248:Carbon Monoxide; D010100:Oxygen; D000111:Acetylcysteine