title: Carbon Monoxide Gas Is Not Inert, but Global, in Its Consequences for Bacterial Gene Expression, Iron Acquisition, and Antibiotic Resistance.
abstract: Carbon monoxide is a respiratory poison and gaseous signaling molecule. Although CO-releasing molecules (CORMs) deliver CO with temporal and spatial specificity in mammals, and are proven antimicrobial agents, we do not understand the modes of CO toxicity. Our aim was to explore the impact of CO gas per se, without intervention of CORMs, on bacterial physiology and gene expression.
  
  
  
  We used tightly controlled chemostat conditions and integrated transcriptomic datasets with statistical modeling to reveal the global effects of CO. CO is known to inhibit bacterial respiration, and we found expression of genes encoding energy-transducing pathways to be significantly affected via the global regulators, Fnr, Arc, and PdhR. Aerobically, ArcA-the response regulator-is transiently phosphorylated and pyruvate accumulates, mimicking anaerobiosis. Genes implicated in iron acquisition, and the metabolism of sulfur amino acids and arginine, are all perturbed. The global iron-related changes, confirmed by modulation of activity of the transcription factor Fur, may underlie enhanced siderophore excretion, diminished intracellular iron pools, and the sensitivity of CO-challenged bacteria to metal chelators. Although CO gas (unlike H2S and NO) offers little protection from antibiotics, a ruthenium CORM is a potent adjuvant of antibiotic activity.
  
  
  
  This is the first detailed exploration of global bacterial responses to CO, revealing unexpected targets with implications for employing CORMs therapeutically.
  
  
  
  This work reveals the complexity of bacterial responses to CO and provides a basis for understanding the impacts of CO from CORMs, heme oxygenase activity, or environmental sources. Antioxid. Redox Signal. 24, 1013-1028.
authors.affiliation: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Wareham
authors.affiliation: 2 School of Informatics, The University of Edinburgh , Edinburgh, United Kingdom .
authors.forename: Ronald
authors.initials: R
authors.lastname: Begg
authors.affiliation: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors.forename: Helen E
authors.initials: HE
authors.lastname: Jesse
authors.affiliation: 3 Molecular Microbial Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Johan W A
authors.initials: JW
authors.lastname: Van Beilen
authors.affiliation: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors.forename: Salar
authors.initials: S
authors.lastname: Ali
authors.affiliation: 4 Biomedical EPR Facility, School of Biological Sciences, University of Essex , Colchester, United Kingdom .
authors.forename: Dimitri
authors.initials: D
authors.lastname: Svistunenko
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.affiliation: 3 Molecular Microbial Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Klaas J
authors.initials: KJ
authors.lastname: Hellingwerf
authors.affiliation: 2 School of Informatics, The University of Edinburgh , Edinburgh, United Kingdom .
authors.forename: Guido
authors.initials: G
authors.lastname: Sanguinetti
authors.affiliation: 1 Department of Molecular Biology and Biotechnology, The University of Sheffield , Sheffield, United Kingdom .
authors.forename: Robert K
authors.initials: RK
authors.lastname: Poole
mesh_terms: D000332:Aerobiosis; D000596:Amino Acids / Q000096:biosynthesis; D000693:Anaerobiosis; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000502:physiology*; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D007501:Iron / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008826:Microbial Sensitivity Tests; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017262:Siderophores / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D017262:Siderophores; D014157:Transcription Factors; D002248:Carbon Monoxide; D007501:Iron