title: CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)3Cl(glycinate)] Actions on a Heme-Deficient Mutant of Escherichia coli.
abstract: OBJECTIVE
  Carbon monoxide-releasing molecules (CORMs) are being developed with the ultimate goal of safely utilizing the therapeutic potential of CO clinically, including applications in antimicrobial therapy. Hemes are generally considered the prime targets of CO and CORMs, so we tested this hypothesis using heme-deficient bacteria, applying cellular, transcriptomic, and biochemical tools.
  
  
  RESULTS
  CORM-3 [Ru(CO)3Cl(glycinate)] readily penetrated Escherichia coli hemA bacteria and was inhibitory to these and Lactococcus lactis, even though they lack all detectable hemes. Transcriptomic analyses, coupled with mathematical modeling of transcription factor activities, revealed that the response to CORM-3 in hemA bacteria is multifaceted but characterized by markedly elevated expression of iron acquisition and utilization mechanisms, global stress responses, and zinc management processes. Cell membranes are disturbed by CORM-3.
  
  
  METHODS
  This work has demonstrated for the first time that CORM-3 (and to a lesser extent its inactivated counterpart) has multiple cellular targets other than hemes. A full understanding of the actions of CORMs is vital to understand their toxic effects.
  
  
  CONCLUSIONS
  This work has furthered our understanding of the key targets of CORM-3 in bacteria and raises the possibility that the widely reported antimicrobial effects cannot be attributed to classical biochemical targets of CO. This is a vital step in exploiting the potential, already demonstrated, for using optimized CORMs in antimicrobial therapy.
authors: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors: Jayne Louise
authors: JL
authors: Wilson
authors: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors: Lauren K
authors: LK
authors: Wareham
authors: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors: Samantha
authors: S
authors: McLean
authors: 2 School of Informatics, The University of Edinburgh , Edinburgh, United Kingdom .
authors: Ronald
authors: R
authors: Begg
authors: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors: Sarah
authors: S
authors: Greaves
authors: 3 Department of Chemistry, The University of Sheffield , Sheffield, United Kingdom .
authors: Brian E
authors: BE
authors: Mann
authors: 2 School of Informatics, The University of Edinburgh , Edinburgh, United Kingdom .
authors: Guido
authors: G
authors: Sanguinetti
authors: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors: Robert K
authors: RK
authors: Poole
mesh_terms: D002248:Carbon Monoxide / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D048168:Escherichia coli K12 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism; D006418:Heme / Q000235:genetics / Q000378:metabolism; D013294:Lactococcus lactis / Q000378:metabolism; D008962:Models, Theoretical; D009154:Mutation; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D029968:Escherichia coli Proteins; D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D006418:Heme; D002248:Carbon Monoxide