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Gallium Potentiates the Antibacterial Effect of Gentamicin against Francisella tularensis
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). (Anders Sjöstedt)
2016 (Engelska)Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 60, nr 1, s. 288-295Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The reasons why aminoglycosides are bactericidal have not been not fully elucidated, and evidence indicates that the cidal effects are at least partly dependent on iron. We demonstrate that availability of iron markedly affects the susceptibility of the facultative intracellular bacterium Francisella tularensis strain SCHU S4 to the aminoglycoside gentamicin. Specifically, the intracellular depots of iron were inversely correlated to gentamicin susceptibility, whereas the extracellular iron concentrations were directly correlated to the susceptibility. Further proof of the intimate link between iron availability and antibiotic susceptibility were the findings that a Delta fslA mutant, which is defective for siderophore-dependent uptake of ferric iron, showed enhanced gentamicin susceptibility and that a Delta feoB mutant, which is defective for uptake of ferrous iron, displayed complete growth arrest in the presence of gentamicin. Based on the aforementioned findings, it was hypothesized that gallium could potentiate the effect of gentamicin, since gallium is sequestered by iron uptake systems. The ferrozine assay demonstrated that the presence of gallium inhibited >70% of the iron uptake. Addition of gentamicin and/or gallium to infected bone marrow-derived macrophages showed that both 100 mu M gallium and 10 mu g/ml of gentamicin inhibited intracellular growth of SCHU S4 and that the combined treatment acted synergistically. Moreover, treatment of F. tularensis-infected mice with gentamicin and gallium showed an additive effect. Collectively, the data demonstrate that SCHU S4 is dependent on iron to minimize the effects of gentamicin and that gallium, by inhibiting the iron uptake, potentiates the bactericidal effect of gentamicin in vitro and in vivo.

Ort, förlag, år, upplaga, sidor
2016. Vol. 60, nr 1, s. 288-295
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-121275DOI: 10.1128/AAC.01240-15ISI: 000369154600036PubMedID: 26503658OAI: oai:DiVA.org:umu-121275DiVA, id: diva2:931844
Tillgänglig från: 2016-05-30 Skapad: 2016-05-30 Senast uppdaterad: 2018-06-07Bibliografiskt granskad

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Lindgren, HelenaSjöstedt, Anders

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Mikrobiologi inom det medicinska området

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