title: Zinc stress induces copper depletion in Acinetobacter baumannii.
abstract: The first row transition metal ions zinc and copper are essential to the survival of many organisms, although in excess these ions are associated with significant toxicity. Here, we examined the impact of zinc and copper stress on Acinetobacter baumannii, a common opportunistic pathogen.
  
  
  
  We show that extracellular zinc stress induces a copper-specific depletion phenotype in A. baumannii ATCC 17978. Supplementation with copper not only fails to rescue this phenotype, but further exacerbates the copper depletion. Extensive analysis of the A. baumannii ATCC 17978 genome identified 13 putative zinc/copper resistance efflux pumps. Transcriptional analyses show that four of these transporters are responsive to zinc stress, five to copper stress and seven to the combination of zinc and copper stress, thereby revealing a likely foundation for the zinc-induced copper starvation in A. baumannii. In addition, we show that zinc and copper play crucial roles in management of oxidative stress and the membrane composition of A. baumannii. Further, we reveal that zinc and copper play distinct roles in macrophage-mediated killing of this pathogen.
  
  
  
  Collectively, this study supports the targeting of metal ion homeostatic mechanisms as an effective antimicrobial strategy against multi-drug resistant bacterial pathogens.
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Hassan
authors.affiliation: Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Victoria G
authors.initials: VG
authors.lastname: Pederick
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia.
authors.forename: Liam D H
authors.initials: LD
authors.lastname: Elbourne
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Paulsen
authors.affiliation: Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia. christopher.mcdevitt@adelaide.edu.au.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McDevitt
authors.affiliation: Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia. bart.eijkelkamp@adelaide.edu.au.
authors.forename: Bart A
authors.initials: BA
authors.lastname: Eijkelkamp
mesh_terms: D000151:Acinetobacter Infections / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001693:Biological Transport, Active; D003300:Copper / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D006801:Humans; D026901:Membrane Transport Proteins / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000494:pharmacology; D013312:Stress, Physiological; D000074084:THP-1 Cells / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D026901:Membrane Transport Proteins; D017382:Reactive Oxygen Species; D003300:Copper; D015032:Zinc
keywords: Acinetobacter; Copper; Fatty acids; Macrophages; Membrane; Oxidative stress; Transporter; Zinc