Synergy between the iron chelator deferoxamine and the antimicrobial agents gentamicin, chloramphenicol, cefalothin, cefotiam and cefsulodin

Asbeck, B. S. Van; Marcelis, J. H.; Kats, J. H. van; Jaarsma, Emmy Y.; Verhoef, J.

doi:10.1007/bf02013900

Cited by 33 publications

(30 citation statements)

References 18 publications

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“…Gallium was found to be an effective competitive antagonist of the iron uptake, and the combined synergistic effects of gallium and gentamicin also supported a scenario where the high uptake of iron was critical for the bacterium to withstand the gentamicinmediated effects. In relation to previous data on the effects of iron chelation and the antibacterial effects of gentamicin, our findings support previously published studies that reported an additive or synergistic effect (16,17). and spleens of mice.…”

Section: Discussionsupporting

confidence: 92%

“…Numerous publications have implied that iron contributes to the bactericidal effect of aminoglycosides; however, the findings have to some extent been contradictory. Some studies implied that ferric iron promoted bacterial death and iron chelation mitigated the antibiotic effect (14,15), whereas other studies indicated that iron chelation acted in synergy with aminoglycosides against various Gram-negative and Gram-positive bacteria (16,17). We observed that the susceptibility of SCHU S4 to gentamicin in vitro was very significantly affected by both the intracellular iron depots and the extracellular availability of iron.…”

Section: Discussionmentioning

confidence: 99%

“…Besides the demonstrations that iron availability affects antibiotic susceptibility, there is also evidence that iron sequestration can potentiate antibiotic-mediated antibacterial effects in vitro. In support of this, several studies have demonstrated synergistic effects between aminoglycosides and iron chelation against multiple Gram-negative and Gram-positive bacteria (16,17). In view of the recent demonstration that Fe-S proteins promote uptake of aminoglycosides, the exact mechanisms behind the documented enhancement of antibiotic effects in vitro by iron chelation are unclear.…”

mentioning

confidence: 90%

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Gallium Potentiates the Antibacterial Effect of Gentamicin against Francisella tularensis

Lindgren

Sjöstedt

2016

Antimicrob Agents Chemother

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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 ⌬fslA mutant, which is defective for siderophore-dependent uptake of ferric iron, showed enhanced gentamicin susceptibility and that a ⌬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 M gallium and 10 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.F rancisella tularensis is the etiological agent of the zoonotic disease tularemia. The bacterium has the capability to infect via many different routes, and the most common clinical manifestation is through vector-borne transmission, which leads to ulceroglandular tularemia (1). Another common route is through inhalation, which leads to respiratory tularemia, the most serious form of the disease (1). There are several subspecies of F. tularensis, and of these, the two clinically important forms are F. tularensis subsp. holarctica and F. tularensis subsp. tularensis (2). The latter is the more virulent form, and in the preantibiotic era, the respiratory form had a case-fatality rate of more than 50%. F. tularensis is a facultative intracellular bacterium capable of infecting many forms of cells; however, by far the most studied interaction is between F. tularensis and monocytic cells (3). As for other intracellular bacteria, the uptake of iron is critical for the successful replication, but in this regard F. tularensis is unusual since previous studies have identified only two iron uptake systems; the ferrous iron (feo) and the ferric siderophore (fsl) systems (4). The exact roles and contributions of these systems for efficient intramacrophage replication of the highly virulent...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

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Gallium Potentiates the Antibacterial Effect of Gentamicin against Francisella tularensis

Lindgren

Sjöstedt

2016

Antimicrob Agents Chemother

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“…[4][5][6] Moreover, iron chelation therapy has been shown to work synergistically with antibiotics in the treatment of murine sepsis. 25,26 Several explanations for the differences with our findings in humans can be put forward. First of all, the majority of studies in which a beneficial effect of iron chelation therapy was found were performed in rodents or in vitro.…”

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confidence: 67%

The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nimmune response, and subclinical organ injury during systemic inflammation induced by experimental endotoxemia in humans in vivo. Methods DesignThis double-blind, randomized, placebo-controlled trial (Clinicaltrials.gov identifier:01349699) was approved by the local ethics committee, and carried out according to standards of Good Clinical Practice and the Declaration of Helsinki. After written informed consent, 30 healthy non-smoking male subjects were randomly treated with either iron loading (iron sucrose), or iron chelation (deferasirox) or placebo, prior to the intravenous administration of 2 ng/kg purified E.Coli endotoxin, as described in detail in the Online Supplementary Methods. Iron loading and iron chelation therapyAt T = -2 h (i.e. 2 h before endotoxin administration), iron chelation therapy (deferasirox (Exjade ® ), Novartis, The Netherlands) or placebo (starch powder) was administered orally. A commonly applied dose of 30 mg/kg of deferasirox 13 was dissolved in water and was stirred until the moment of intake. Subjects drank the suspension within 1 min. The time point of deferasirox administration was chosen so that maximal plasma levels were achieved between 0 and 2 h after endotoxin administration, just before and during the expected peak of the pro-inflammatory cytokine response. At T = -1 h, a generally applied therapeutic dose 14 of 1.25 mg/kg iron sucrose (Venofer ® , Vifor Nederland BV, The Netherlands), or placebo (NaCl 0.9%), was intravenously administered through blinded syringes and lines. Because the two therapies had different administration routes, a double dummy was used to ensure adequate blinding. Iron homeostasis analysisSerum iron, ferritin, transferrin and soluble transferrin receptor (sTfR), hepcidin, GDF-15 and LPI were determined as described in the Online Supplementary Design and Methods. Oxidative stress and cytokine measurementsOxidative stress (malondialdehyde) and plasma levels of proinflammatory cytokines TNF-α and IL-6, the anti-inflammatory cytokines IL-10 and IL-1ra, and markers of endothelial activation Vascular Cell Adhesion Molecule (VCAM) and Intercellular Adhesion Molecule (ICAM) were determined as described in the Online Supplementary Design and Methods. Subclinical organ injurySubclinical endothelial injury was assessed by measuring the changes in response of the forearm vasculature to the infusion of vasoactive medication into the brachial artery, using venous occlusion plethysmography. For the determination of subclinical renal tubular damage, urinary Glutathione S-Transferase Alpha-1-1 (GSTA1-1) and Glutathione S-Transferase-Pi-1-1 (GSTP1-1) were determined. A detailed description is provided in the Online Supplementary Design and Methods. Stastistical analysisData are expressed as mean±SEM, or median (25th-75th percentile), depending on their distribution. P=0.05 was considered statistically significant. For all outcome variables, the intervention groups were compared to the placebo group in two ...

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“…They are lowmolecular-weight chelating agents that form stable complexes with iron [11,12]. There are many reports of the antimicrobial activity of chelating agents with different chemical structures [13][14][15][16][17][18][19]. Kojic acid (5-hydroxy-2-hydroxymethyl-pyran-4-one) and 3-hydroxypyranones, derivatives of it are examples of these compounds [13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives

Fassihi

Abedi

Saghaie

et al. 2009

European Journal of Medicinal Chemistry

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Synergy between the iron chelator deferoxamine and the antimicrobial agents gentamicin, chloramphenicol, cefalothin, cefotiam and cefsulodin

Cited by 33 publications

References 18 publications

Gallium Potentiates the Antibacterial Effect of Gentamicin against Francisella tularensis

Gallium Potentiates the Antibacterial Effect of Gentamicin against Francisella tularensis

The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

Synthesis, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives

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