title: The antibacterial activity of Ga3+ is influenced by ligand complexation as well as the bacterial carbon source.
abstract: Gallium ions have previously been shown to exhibit antibacterial and antibiofilm properties. In this study, we report differential bactericidal activities of two gallium complexes, gallium desferrioxamine B (Ga-DFOB) and gallium citrate (Ga-Cit). Modeling of gallium speciation in growth medium showed that DFOB and citrate both can prevent precipitation of Ga(OH)(3), but some precipitation can occur above pH 7 with citrate. Despite this, Ga-Cit 90% inhibitory concentrations (IC(90)) were lower than those of Ga-DFOB for clinical isolates of Pseudomonas aeruginosa and several reference strains of other bacterial species. Treatment with Ga compounds mitigated damage inflicted on murine J774 macrophage-like cells infected with P. aeruginosa PAO1. Again, Ga-Cit showed more potent mitigation than did Ga-DFOB. Ga was also taken up more efficiently by P. aeruginosa in the form of Ga-Cit than in the form of Ga-DFOB. Neither Ga-Cit nor Ga-DFOB was toxic to several human cell lines tested, and no proinflammatory activity was detected in human lung epithelial cells after exposure in vitro. Metabolomic analysis was used to delineate the effects of Ga-Cit on the bacterial cell. Exposure to Ga resulted in lower concentrations of glutamate, a key metabolite for P. aeruginosa, and of many amino acids, indicating that Ga affects various biosynthesis pathways. An altered protein expression profile in the presence of Ga-Cit suggested that some compensatory mechanisms were activated in the bacterium. Furthermore, the antibacterial effect of Ga was shown to vary depending on the carbon source, which has importance in the context of medical applications of gallium.
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden. olena.rzhepishevska@chem.umu.se
authors.forename: Olena
authors.initials: O
authors.lastname: Rzhepishevska
authors.forename: Barbro
authors.initials: B
authors.lastname: Ekstrand-Hammarström
authors.forename: Maximilian
authors.initials: M
authors.lastname: Popp
authors.forename: Erik
authors.initials: E
authors.lastname: Björn
authors.forename: Anders
authors.initials: A
authors.lastname: Bucht
authors.forename: Anders
authors.initials: A
authors.lastname: Sjöstedt
authors.forename: Henrik
authors.initials: H
authors.lastname: Antti
authors.forename: Madeleine
authors.initials: M
authors.lastname: Ramstedt
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002244:Carbon / Q000378:metabolism*; D002460:Cell Line; D002951:Citrates / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D003470:Culture Media; D003676:Deferoxamine / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology; D005708:Gallium / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005710:Gallium Radioisotopes / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008024:Ligands; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D002951:Citrates; D003470:Culture Media; D005710:Gallium Radioisotopes; D008024:Ligands; D002244:Carbon; D005708:Gallium; C103850:gallium citrate; D003676:Deferoxamine