Synergy between the iron chelator deferoxamine in the presence or absence of ascorbic acid and gentamicin, chloramphenicol, cephalothin, cefotiam or cefsulodin, used against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, proteus mirabilis and species of Salmonella, Enterobacter, Pseudomonas and Providencia, was determined by measuring the effect of the drugs and combination of drugs on growth of the bacteria in an automated turbidimeter. The combination of drugs was considered to be synergistic when the growth inhibiting effect of the combination was greater than that of the combined action of each of the drugs separately. Deferoxamine plus ascorbic acid together with either gentamicin or cefsulodin showed synergy in 10 out of 10, and 5 out of 6 cultures respectively, whereas deferoxamine plus ascorbic acid with chloramphenicol, cephalothin or cefotiam was synergistic in 6 out of 14, 5 out of 11, and 3 out of 6 cultures. This synergistic effect was much lower when microorganisms were incubated with deferoxamine combined with the various antibiotics but without ascorbic acid. Ascorbic acid alone had no synergistic effect. When deferoxamine was saturated with iron, its antibacterial effect was completely abolished.
It has been shown that iron (III) impairs the function of polymorphonuclear granulocytes (PMN). We have studied the effect of iron (II), on the membrane function of PMN, by assessing the uptake of radiolabelled Staphylococcus aureus by these cells. Iron (II), significantly impaired PMN phagocytic function. Addition of ascorbic acid reduced uptake further. Ferrous ascorbate, molar ratio 1:20, impaired phagocytic capacity of PMN significantly at iron concentrations as low as 1-10 microM. The toxic effect of iron (II) was not observed when desferrioxamine or transferrin was present in the incubation medium. The oxygen-free radical scavengers thiourea, mannitol and catalase prevented toxicity mediated by ferrous ammoniumsulphate but not by ferrous ascorbate (molar ratio of 1:20). Although high concentrations of ascorbic acid inhibited the generation of .OH and also the formation of the DMPO-.OH adduct by zymosan stimulated PMN, toxicity of iron increased. Iron (II) impaired the uptake of S. aureus by PMN of a patient with chronic granulomatous disease while iron (III) did not. Iron mediated impairment of PMN function is not only a result of the generation of toxic oxygen metabolites but also of direct interaction of iron (II) or an iron (II)-oxygen intermediate with molecules of the cell membrane.
Summary. The effect of human serum on Escherichia coli was studied with serumsensitive and serum-resistant strains. The bactericidal effect of human serum on serumsensitive strains of E. coli depended on the activation of the classical complement pathway. The role of activation of the alternative pathway was less important. After incubation in sub-bactericidal concentrations of serum these strains were also easily phagocytosed by polymorphonuclear leukocytes (PMNL). Strains of E. coli of certain 0-types required not only an intact classical pathway but also the presence of specific antibodies for effective killing by serum and effective phagocytosis by PMNL, despite rapid activation of complement and rapid deposition of C3 on the bacterial surface in the absence of antibody. Capsulate strains O l K l and 078K80 resisted the bactericidal effect of serum even in the presence of specific antibodies; phagocytosis by PMNL only occurred after opsonisation with specific antibodies.
In a previous study we showed that the phagocytic function of non-stimulated PMN was impaired after incubation with high concentrations (200 microM) of polynuclear Fe(III), probably as a result of continuous generation of small amounts of superoxide and subsequent formation of hydroxyl radicals (Van Asbeck et al, 1984b). Because polynuclear Fe(III) complexes may not be available for biological reactions we have studied the effects of polynuclear and mononuclear iron(III) on the PMN. Fe(III) in its polynuclear form (Fe:citrate 1:1) was deleterious for the phagocytic function of PMN, while the mononuclear form (Fe:citrate 1:20) was not toxic. Binding affinity of polynuclear Fe(III) for PMN was higher than of mononuclear Fe(III), and a considerable amount of bound Fe(III) was found in the cytosolic fraction of non-stimulated PMN. Limit dilution analysis of polynuclear complexes revealed that concentrations as low as 25 microM Fe(III) significantly impaired phagocytic function. The molecular weight of these complexes is similar to that of the non-transferrin plasma iron found in the serum of patients with iron overload. The toxic effects of small polynuclear non-transferrin plasma Fe(III) complexes on PMN function may contribute to the development of infections in patients with iron overload.
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