title: Analysis of the bacterial response to Ru(CO)3Cl(Glycinate) (CORM-3) and the inactivated compound identifies the role played by the ruthenium compound and reveals sulfur-containing species as a major target of CORM-3 action.
abstract: OBJECTIVE
  Carbon monoxide (CO)-releasing molecules (CO-RMs) are being developed with the ultimate goal of safely utilizing the therapeutic potential of CO clinically. One such application is antimicrobial activity; therefore, we aimed to characterize and compare the effects of the CO-RM, CORM-3, and its inactivated counterpart, where all labile CO has been removed, at the transcriptomic and cellular level.
  
  
  RESULTS
  We found that both compounds are able to penetrate the cell, but the inactive form is not inhibitory to bacterial growth under conditions where CORM-3 is. Transcriptomic analyses revealed that the bacterial response to inactivated CORM-3 (iCORM-3) is much lower than to the active compound and that a wide range of processes appear to be affected by CORM-3 and to a lesser extent iCORM-3, including energy metabolism, membrane transport, motility, and the metabolism of many sulfur-containing species, including cysteine and methionine.
  
  
  METHODS
  This work has demonstrated that both CORM-3 and its inactivated counterpart react with cellular functions to yield a complex response at the transcriptomic level. A full understanding of the actions of both compounds is vital to understand the toxic effects of CO-RMs.
  
  
  CONCLUSIONS
  This work has furthered our understanding of how CORM-3 behaves at the cellular level and identifies the responses that occur when the host is exposed to the Ru compound as well as those that result from the released CO. This is a vital step in laying the groundwork for future development of optimized CO-RMs for eventual use in antimicrobial therapy.
authors.affiliation: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors.forename: Samantha
authors.initials: S
authors.lastname: McLean
authors.forename: Ronald
authors.initials: R
authors.lastname: Begg
authors.forename: Helen E
authors.initials: HE
authors.lastname: Jesse
authors.forename: Brian E
authors.initials: BE
authors.lastname: Mann
authors.forename: Guido
authors.initials: G
authors.lastname: Sanguinetti
authors.forename: Robert K
authors.initials: RK
authors.lastname: Poole
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000693:Anaerobiosis; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D016680:Genome, Bacterial; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology*; D010101:Oxygen Consumption; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D009942:Organometallic Compounds; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; C476530:tricarbonylchloro(glycinato)ruthenium(II)